Incidence and mortality

Cervical cancer is the third most common cancer among women worldwide and the fourth leading cause of cancer deaths in females, with an estimated 529,800 new cases and 275,100 deaths in the year 2008.¹ The incidence of cervical cancer in developing countries remains nearly twice that in developed countries, with the highest rates observed in Africa, South-Central Asia, and South America (29 per 100,000 per year) and the lowest in Western Asia, Australia/New Zealand, and North America (7.5 per 100,000 per year).² In the United States, it is estimated that there will be 12,900 new cases of cervical cancer in 2015, with 4100 related deaths.³ Cervical cancer is frequently seen in the Hispanic population (10.5% of all cases of cervical cancer) followed by the African-American population (10.2%), American Indians (9.5%), whites (7.1%), and Pacific Islanders/Asian (6.4%).³

In the past 40 years, primarily because of the introduction of screening with the Pap smear, the incidence and mortality rates for cervical cancer have declined in most developed countries.⁴ In the United States; incidence rates have declined nearly by 70% during this period. Rates of invasive cancer per 100,000 females have declined from 10.2 in 1998 to 8.5 in 2002.⁵ In developing countries, however, cervical cancer continues to be a significant health problem owing to suboptimal screening programs and a lack of therapy for precancerous conditions.

There are no reliable data on the prevalence and incidence of precancerous cervical lesions. In the United States, the National Cancer Institute (NCI) estimates that each year approximately 300,000 women are found to have premalignant cervical lesions, whereas the American Cancer Society reported that in 2001, an estimated 65,000 women were found to have carcinoma in situ (CIS) of the cervix. From the SEER data, the overall incidence of squamous cell CIS among whites is 41.4 per 100,000 woman-years from 1991 to 1995.⁶

Risk factors for cervical neoplasia

Summary

Cervical neoplasia continues to be a major health problem worldwide. Higher incidence and mortality rates are observed in developing countries. Among more developed countries, a significant decline in incidence and mortality has been observed in the past 50 years, which has been attributed to the introduction of screening programs. Current epidemiologic data support a strong role for HPV infection in the etiology of cervical neoplasia. This association satisfies all criteria for causality in epidemiologic research: strength, consistency, and specificity of the association; dose–response and temporal relationship; and biologic plausibility.¹¹ HPV infection appears to explain many of the established risk factors for cervical neoplasia, including sexual behavior and cigarette smoking. Nonetheless, the high prevalence of HPV infection in young healthy women compared with the low incidence of cervical neoplasia and the low progression rate of untreated CIN lesions support the existence of other cofactors in cervical carcinogenesis.⁴⁴ Future epidemiologic studies will need to further assess the role of these cofactors and their interaction with HPV. In addition, the role of viral factors such as HPV persistence and HPV variants in the progression of cervical neoplasia as well as of the determinant factors of HPV persistence will require further evaluation.⁴⁵ Similarly, the impact of recent trends in environmental factors such as smoking, exogenous hormones, and dietary factors deserves further attention.⁷

Squamous cell carcinoma

The majority of cervical carcinomas are squamous cell carcinomas, which are classified as either large cell nonkeratinizing or large cell keratinizing. Nonkeratinizing carcinoma is characterized by squamous cells with somewhat hyperchromatic nuclei and a moderate amount of cytoplasm growing in discrete nests separated by stroma (Figure 1). In the center of some of the nests, the squamous cells appear to differentiate and degenerate. Keratinizing carcinoma is characterized by cells with very hyperchromatic nuclei and densely eosinophilic cytoplasm growing in irregular invasive nests. Many of these nests have central “pearls” that contain abundant keratin. The average age of patients with squamous cell carcinoma is 51.4 years. Selected variants of squamous cell carcinoma are described in the following paragraphs.

Papillary squamous cell carcinoma

Papillary squamous cell carcinomas of the uterine cervix with transitional or squamous differentiation often resemble transitional cell carcinomas of the urinary tract (Figure 2). Urinary tract transitional cell carcinomas have a cytokeratin profile strongly positive for cytokeratin 20, whereas primary genital tract transitional cell carcinomas stain positive for cytokeratin 7.⁴⁸ Invasive papillary transitional cell carcinomas of the uterine cervix are potentially aggressive carcinomas. It is important to distinguish these carcinomas from benign squamous papillomas and condyloma acuminata.⁴⁹ Biopsy material must include the underlying stroma to permit identification of invasion.

Lymphoepithelioma-like carcinoma

Lymphoepithelioma-like carcinomas are histologically similar to lymphoepitheliomas arising in the nasopharynx and salivary glands (Figure 3). These carcinomas are usually well circumscribed and composed of undifferentiated cells. The cancer cells are surrounded by inflammatory infiltrates composed of lymphocytes, plasma cells, and eosinophils.⁵⁰ Hasumi and colleagues reported 39 cases from the Cancer Institute Hospital in Tokyo. Their patients, 72% of whom were younger than 50 years of age, were treated with radical hysterectomy and pelvic lymphadenectomy. Two patients had positive lymph nodes. At the time of the report, 38 of the 39 patients were alive. The single death occurred 5 months after surgery and was due to serum hepatitis.

Adenocarcinoma

Adenocarcinomas represent 20–25% of cervical carcinomas today, whereas from 1950 to 1960, they represented only 5%.⁵¹ This change in prevalence is a worldwide phenomenon.⁵² The mean age at diagnosis for patients with invasive adenocarcinoma is between 47 and 53 years. Selected variants of adenocarcinoma are described in the following paragraphs.

Mucinous adenocarcinoma is the most common type of cervical adenocarcinoma.⁵³ In the WHO classification, the first type of mucinous adenocarcinoma is composed of cells that resemble the columnar cells of the normal endocervical mucosa and is referred to as the endocervical type (Figure 4). The second type is termed the intestinal type because it is composed of cells similar to those present in adenocarcinomas of the large intestine. A third type is composed of signet-ring cells and designated the signet-ring type. Frequently, mucinous adenocarcinomas are a mixture of these cell types.

Endometrioid adenocarcinoma is the second most common type of primary endocervical tumor, accounting for 30% of all primary endocervical tumors. Endometrioid adenocarcinomas resemble typical endometrioid adenocarcinoma arising from the endometrial cavity (Figure 5). Identification of the site of origin (i.e., whether the primary tumor is in the endocervix or endometrium) may be difficult, but proper identification is important as the site or origin significantly influences therapy.

Adenoma malignum is difficult to distinguish cytologically from normal endocervical glands (Figure 6) and is referred to as minimal-deviation adenocarcinoma. A distinguishing feature of adenoma malignum is a bizarre and irregular glandular branching pattern. These irregular glands invade deeply into the stroma, and diagnosis requires a large tissue specimen from a cone biopsy or hysterectomy specimen. Adenoma malignum is extremely rare and is sometimes associated with Peutz–Jegher syndrome.⁵⁴ The survival rate is poor if the well-differentiated pattern leads to under treatment.

Other epithelial tumors

Adenosquamous carcinoma is defined as a cancer that contains an admixture of histologically malignant squamous and glandular cells.⁵⁵ Adenosquamous carcinomas account for 5–25% of the cervical carcinomas in some series.^{56, 57} These carcinomas are similar in their clinical presentation, epidemiology, and pattern of spread to squamous cell carcinomas and adenocarcinomas. The poorly differentiated form of adenosquamous carcinoma can be made up of large uniform polygonal cells with a finely granular cytoplasm of the ground-glass type, hence the term “glassy cells” (Figure 7). Similar to other undifferentiated tumors, glassy cell carcinomas spread early and are aggressive.⁵⁷ The mucoepidermoid carcinoma, also placed in this category, contain large cell nonkeratinizing or focally keratinizing squamous carcinoma, which stains positive for mucin but lacks recognizable glands. The mucinous component includes goblet or signet-ring-type cells localized in a nest of squamous cells. These carcinomas represent 20% of the carcinomas in some series if mucin is measured.

Small cell neuroendocrine carcinoma contains small anaplastic cells with scant cytoplasm (Figure 8). These highly aggressive cancers diffusely infiltrate the cervical stroma.⁵⁸ Staining reveals neuroendocrine markers in most cases. Women with small cell carcinoma are likely to be 10 years younger than those with squamous cell carcinoma. Small-cell carcinomas are frequently associated with widespread metastasis to multiple sites, including bone, liver, skin, and brain. These tumors should not be confused with small squamous cell carcinomas, which are associated with a better prognosis. Efforts to treat these cancers with approaches typically used for small cell carcinomas of the lung have had mixed results.

Non-small cell neuroendocrine carcinoma

Nonsmall cell neuroendocrine carcinomas of the cervix have been reported, but they are not listed in the current WHO classification of cervical tumors.⁵⁹ The tumors contain intermediate to large cells, high-grade nuclei, and eosinophilic cytoplasmic granules of the type seen in neuroendocrine cells. A trabecular pattern is frequently evident, with or without glandular differentiation (Figure 9). Tumors are usually immunoreactive for chromogranin. Reported survival rates for patients with these aggressive carcinomas are similar to those for patients with small cell carcinoma.

Management of low-grade cytologic abnormalities

Low-grade cytologic abnormalities are usually treated first with antibiotics and repeating the smear several months later. If the smear result regressed to normal, the patient is scheduled for an annual Pap smear screening, whereas patients whose smears remained abnormal are referred for colposcopic evaluation, and Pap test every 4–6 months for 2 years. After three consecutive negative smears in the 2-year follow-up period, patients can be monitored using a routine cervical cancer screening protocol.^{68, 69} For patients with clinical suspicion of cancer or persistent abnormal Pap smears during the 2-year follow-up, colposcopic evaluation is recommended. Recommended management form ASCCP for women with ASCUS or LGSIL Paps is based on age. For women aged 21–24 years with ASCUS or LGSIL, the recommendation is to repeat cytology at 12 months. For older women with LGSIL Pap and no HPV testing or positive HPV testing, recommendation is to proceed with colposcopy (Figure 12).⁶⁷

In view of the costs, both emotional and economic, associated with evaluating women with low-grade cytologic abnormalities, considerable interest has arisen in developing novel cost-effective triage strategies for these patients. HPV DNA testing, automated cytology screening, and cervicography are being evaluated as adjunct methods in the assessment and triage of patients with low-grade cytologic abnormalities. Most research has focused on the assessment of HPV testing.

Several researchers have assessed the value of HPV DNA testing as a specific and economical alternative for triage of low-grade cytologic abnormalities and as an adjunct to cervical cytology in primary screening.^70–73 With second-generation HPV DNA detection methods, including PCR-based methods and the hybrid capture HPV DNA assay, both of which have a higher sensitivity and detect a broader range of HPV types with high oncogenic risk than earlier methods, results have been more consistent, supporting the role of HPV typing in the triage of patients with low-grade cytologic abnormalities and as an adjunct to cytology in primary screening.^70–73

New data on HPV primary screening from the ATHENA trial were presented to the FDA in the spring of 2014 supporting the evidence that HPV testing alone is an excellent alternative screening strategy.⁷⁴ More experience and data analysis pertaining to this new strategy will permit a more formal ACS evaluation in the future.

The preferences of clinician and patient and cost considerations should dictate the choice of treatment of CIN, but proper management of LGSILs is expected to remain a fiercely debated question. Although management guidelines have increasingly included nontreatment of LGSILs as an option for patients who may be reliable for long-term follow-up, concerns over legal responsibility for progressive lesions continue to drive intensive follow-up protocols, particularly in the United States, that may not be cost-efficient.⁷⁵ Guidelines recently published may be helpful to follow.

Management of high-grade cytologic abnormalities

Optimal management of HGSILs includes colposcopic evaluation and biopsy or in women older than 24 years of age to proceed to a loop electrical excision procedure (LEEP) without performing colposcopic evaluation. The consensus is that HGSILs should be treated once diagnosed.⁷⁶ For biopsy-proven HGSILs with negative findings on endocervical curettage (ECC), a satisfactory colposcopy examination, and congruent Pap smear and biopsy results, ablation of the transformation zone has been the standard of care for several decades. Three outpatient therapies are used in the United States for treating these lesions: cryotherapy, laser ablation, and LEEP. For patients with unsatisfactory colposcopic examination findings, a Pap smear result more severe than the biopsy findings, the presence of an adenomatous component, suspicion of invasive cancer, or positive findings on ECC, a cone biopsy is indicated. Cone biopsies (talked about later in the chapter) remove tissue to a depth of 20–30 mm and up to 30 mm in diameter, including the transformation zone.

The three outpatient therapies of cryotherapy, laser vaporization, and LEEP have been the focus of controversy. Safety, efficacy, and cost issues have dominated the debate. Cryotherapy, introduced in 1972, was the first outpatient treatment of CIN and remains a dependable treatment because of its reliability, low complication rate, ease of use, and low cost.⁷⁷ Another advantage of cryotherapy is that leaving a large dead viral HPV load within disrupted cells may improve the immune response to the causative agent of CIN. Major disadvantages include lack of ability to tailor treatment to the size of the lesion, lack of a tissue specimen, and the risk of treatment of undetected invasive lesions. Eligible for cryotherapy are patients with satisfactory findings on colposcopic examination, negative findings on ECC, and small lesions (2.5–3.0 cm in diameter) that allow the entire lesion and transformation zone to be covered by the cryotherapy probe.

Laser vaporization was introduced in 1977. It has the advantage of being easily tailored to lesion size, but the cost of the equipment and the lack of a tissue specimen are major disadvantages.⁷⁷ In addition, laser vaporization requires more training and skills than the other two procedures and is associated with more serious safety issues (eye injuries and inadvertent burns). Candidates for this procedure are patients with large CIN lesions, young women with suspicious or invasive lesions or adenocarcinoma in situ in whom preservation of fertility is desired, and patients unwilling to undergo LEEP under local anesthesia.

LEEP was introduced in 1989, and it is currently the technique of choice for the treatment of HGSILs. LEEP is reliable and easy to use. It can be tailored to lesion size and provides a tissue specimen.⁷⁷ The advantage of this last characteristic is underscored by the finding of unsuspected adenocarcinoma in situ and microinvasive squamous cell carcinoma in 2–4% of LEEP specimens.^{67, 77} LEEP, however, has the potential to result in unintentional removal of excessive cervical stroma and removal of disease-free tissue (more frequent when LGSILs are treated). Other disadvantages include its high cost and the increased risk of bleeding and infection. Bleeding after LEEP has been reported in 2–7% of cases.⁷⁷ The high rates of overtreatment observed with LEEP have been related to misdiagnosis of abnormality and multiple punch biopsies of small lesions before treatment.⁶⁷ The use of LEEP in see-and-treat protocols has been shown to improve patient compliance with treatment when patient selection is adequate. This strategy has been suggested as having the greatest potential benefit for populations with poor treatment compliance.⁶⁷

No statistically significant differences in success rates (based on recurrence and persistence) between cryotherapy and laser vaporization have been reported, but variability in these rates from study to study is striking.^{77, 78}

Prevention

Clinical symptoms

The clinical symptoms of carcinoma of the cervix are vaginal bleeding, discharge, and pain. The growth pattern of the carcinoma plays a role in the development of symptoms. Exophytic carcinomas bleed earlier in a sexually active patient (because of contact) than lesions that expand the cervix. Lesions that expand the endocervix in a barrel-shaped configuration may leave the squamous epithelium of the exocervix intact until the lesions exceed 5 or 6 cm in transverse diameter; therefore, carcinomas with this growth pattern may be silent and grow large before the patient bleeds. Cytologic findings may be negative unless the endocervix is sampled with a brush device. Ulcerative lesions that destroy the exocervix bleed early, and necrosis and infection induced by the cancer’s outgrowing its blood supply result in a foul-smelling vaginal discharge.

Severe pelvic pain experienced during the pelvic examination may indicate salpingitis. Tubal infections require management before radiation therapy. Patients with an adnexal mass need surgical treatment before radiation therapy is started.

Paracervical extension of a carcinoma may remain silent until fixation to the pelvic wall occurs. Fixation with or without nodal involvement may obstruct a ureter. Ureteral encroachment is usually a silent process. Patients may present with bilateral ureteral obstruction with impending renal failure and report no history of urinary system complaints. Direct invasion of branches of the sciatic nerve roots causes back pain, and encroachment on the pelvic wall veins and lymphatics causes edema of a lower extremity. The triad of back pain, leg edema, and a nonfunctioning kidney is evidence of an advanced carcinoma with extensive pelvic wall involvement.

The anatomic position of the bladder, so closely adjacent to the cervix, favors contiguous spread from the cervix to the bladder. Urinary frequency and urgency are early manifestations of such spread; patients with advanced disease may present with hematuria or incontinence, suggesting direct extension of tumor to the bladder. Cystoscopy and biopsy should confirm the cause of hematuria or incontinence.

In contrast, posterior extension to the rectum and disruption of the rectal mucosa is an unusual pattern of disease spread in untreated patients. The deep cul-de-sac provides anatomic separation of the rectum and cervix. In patients who present with rectal mucosal involvement, there is usually extensive involvement of the posterior vaginal wall with direct extension to the rectum. For staging and treatment planning, cystoscopy and sigmoidoscopy are essential.

Metastatic carcinoma in para-aortic nodes may extend through the node capsule and directly invade the vertebrae and adjacent nerve roots. Back pain owing to involvement of the lumbar vertebrae and psoas muscles may be a manifestation of massive nodal disease; however, hematogenous spread to the lumbar vertebrae and involvement of the psoas muscle without significant nodal disease may occur.

Diagnosis

The diagnosis of cervical carcinoma is made by pathologic examination of a tissue specimen. A biopsy sample taken from the periphery of a tumor is more likely to contain morphologically intact neoplastic cells that are best able to represent the tumor pathologically. A biopsy specimen taken from the center of a tumor mass may include necrotic tumor debris; the result of hypoxia induced by the tumor’s outgrowing its blood supply. Therefore, to rely on these dead and distorted cells is to compromise the accuracy of the histologic interpretation.

The endocervix should be curetted if no lesion is visible or if the cervix is enlarged, nodular, or hard. Older patients with adenocarcinoma require an endometrial biopsy. It may be difficult to distinguish an endocervical primary tumor from an endometrial primary tumor involving the lower uterine segment.

Patients with an abnormal Pap smear and no visible lesion require colposcopy and biopsy. The tissue specimen may be a simple colposcopy-directed biopsy specimen, an endocervical specimen obtained with a curette, or a conization specimen.

It is the current recommendation of FIGO to classify as stage IA any invasive cancer that can be identified only with a microscope. All gross lesions, even with superficial invasion, are at least stage IB cancers. Vascular space involvement, either venous or lymphatic, should not alter staging. Many clinicians prefer to use the term microinvasion and use criteria recommended by the Society of Gynecologic Oncologists instead of using the FIGO staging system. Microinvasion is invasion limited to 3 mm in depth, is measured from the base of the squamous or glandular epithelium of origin, and does not encompass lymphatic or vascular space involvement. A simple punch biopsy is inadequate for making the diagnosis of microinvasion: a conization specimen, containing the entire neoplastic process, is necessary. Additional tissue is required from patients with positive cone margins because an occult, frankly invasive carcinoma may lie adjacent to a positive margin.

Evaluation and staging

Successful therapy planning requires detailed evaluation of the patient’s general medical condition and the size and extent of the carcinoma. Medical illness must be stabilized and anemia must be corrected before treatment commences. Patients with anemia, which has been extensively studied, have a higher local relapse rate than patients with a normal hemoglobin (Table 2).^{96, 97} The patient’s surgical history is important, and operative notes may describe the status of the abdominal organs as well as report abdominal and pelvic operations. Diagnoses of importance to therapy planning include ulcerative bowel disease, diverticulitis, and pelvic inflammatory disease. Such inflammatory conditions induce adhesions and fix loops of the intestines to each other, the adjacent organs, and the peritoneal surfaces.

Relapse rates for patients with stage IIB or III cancer of the cervix according to average hemoglobin level during radiation therapy. p Values: p = 0.002 (local), p = 0.1 (distant), p = 0.0007 (total).

Source: Bush 1986.⁹⁶ Reproduced with permission of Elsevier.

Patients with small stage I carcinomas should undergo chest radiography, a complete blood count, urinalysis, and blood chemistry analysis before treatment. Patients with advanced carcinomas require cystoscopy and proctoscopy. It is important to apply the FIGO rules for clinical staging (Table 3).⁹⁸ It is clearly stated in the FIGO guidelines that for staging purposes, the following examinations are permitted: cystoscopy, inspection, colposcopy, ECC, hysteroscopy, proctoscopy, intravenous pyelography, chest radiography, and skeletal radiography.⁹⁹ Findings from examinations such as lymphangiography, laparotomy, laparoscopy, computed tomography (CT), magnetic resonance imaging (MRI), and other examinations unnamed by FIGO should not be the basis for changing the clinical stage, despite the fact that such examinations or procedures can provide valuable information for planning therapy. The tumor-nodes-metastasis (TNM) staging categories have also been accepted by FIGO.¹⁰⁰ Lymph node status is not addressed in the FIGO staging system for carcinoma of the cervix, but three radiologic imaging techniques are available to evaluate lymph node status: CT, MRI, and fluorodeoxyglucose-positron emission tomography (FDG-PET) detect abnormal lymph nodes more lymphangiography.

Abbreviation: FIGO, International Federation of Gynecology and Obstetrics.

Source: From Ref. 98.

The best radiologic imaging technique for detecting lymph node metastases is unclear. CT and MRI are good in identifying enlarged nodes; however, the accuracy of these techniques in the detection of positive nodes is compromised by their failure to detect small metastases, and many enlarged nodes are not due to metastases, but inflammation associated with advanced disease. The accuracy of MRI in the detection of lymph node metastases (72–93%) is similar to that of CT; however, when compared with surgical findings, MRI is superior to CT, clinical examination, and sonography in the evaluation of tumor location, tumor size, depth of stromal invasion, vaginal extension, and parametrial extension of cervical cancer.^101–104 Furthermore, studies suggest that MRI is a cost-effective method of evaluating cervical cancers.¹⁰⁴ Figure 13 shows an MRI of a patient with a cervical tumor.

PET or PET/CT is the rapidly expanding modality in oncologic imaging (Figure 14). In a study of 101 patients with carcinoma of the cervix, Grigsby and colleagues reported that CT demonstrated enlarged pelvic lymph nodes in 20% and enlarged para-aortic lymph nodes in 7%, while PET demonstrated abnormal FDG uptake in pelvic lymph nodes in 67%, abnormal FDG uptake in para-aortic lymph nodes in 21%, and abnormal FDG uptake in supraclavicular lymph nodes in 8%.¹⁰⁵ The 2-year progression-free survival rate (PFS), based solely on para-aortic lymph node status, was 64% in CT-normal and PET-normal patients, 18% in CT-normal and PET-abnormal patients, and 14% in CT-abnormal and PET-abnormal patients. The authors concluded that often CT and that the findings on PET are a better predictor of survival than those on CT in patients with carcinoma of the cervix. Further studies are needed to confirm these results and determine if PET imaging is better than surgical staging particularly for determining if patients have positive para-aortic nodes.

In some patients, surgical examination of the lymph nodes is warranted. The risk of occult para-aortic metastases is highest in patients with grossly involved pelvic nodes, and these patients may be the best candidates for operative exploration. These patients also may benefit from removal of the grossly enlarged nodes, which may be difficult to control with radiation alone.¹⁰⁶ When lymph node metastases are sought surgically, the extraperitoneal approach is currently the preferred technique.¹⁰⁷ It is preferred because high complication rates resulted from using a transperitoneal approach followed by radiation therapy.¹⁰⁸ Lymph node exploration and dissection may also be performed using a laparoscopic approach, which is associated with a shorter postoperative recovery time and probably less late radiation morbidity than open transperitoneal staging.¹⁰⁹

Prognostic factors

FIGO stage correlates with survival and control of pelvic disease in patients with cervical cancer; however, prognosis is also influenced by other factors, including tumor characteristics and patient characteristics that are not included in the FIGO staging system.

Tumor size and local extent

Tumor size is one of the most important predictors of local recurrence and death in patients with cervical cancer treated with surgery or radiation therapy (Figure 15). The FIGO staging classification for stage I disease was recently modified to include tumor diameter (i.e., ≤4 cm, stage IB1; >4 cm, stage IB2).⁹⁸ For patients with more advanced disease, other estimates of tumor bulk that correlate with prognosis include presence of medial versus lateral parametrial involvement in FIGO stage IIB disease and unilateral versus bilateral pelvic wall involvement in FIGO stage IIIB disease.^{111, 112}

In patients who have had a radical hysterectomy, histologic evidence of extracervical spread (≥10 mm) and deep stromal invasion (>70% invasion) are associated with a poorer prognosis, as is parametrial extension, which is associated with higher rates of lymph node involvement, local recurrence, and death from cancer.^{91, 113, 114, 115} Uterine body involvement is associated with an increased rate of distant metastases in patients treated with radiation or surgery.¹¹⁶

Surgical treatment options

Outcomes after surgical treatment

Reported 5-year survival rates for women with stage IB cervical cancer treated with radical hysterectomy and pelvic lymphadenectomy are approximately 80–90% (Table 4).^{89, 90, 91, 168, 169, 170, 171, 172, 173, 174, 175, 176} Patients with positive surgical margins or positive lymph nodes are at the highest risk of recurrence and poor outcome. Delgado et al.,⁹¹ in a large prospective study, reported 3-year DSS rates of 85.6% in patients with negative nodes and 50–74% in patients with positive nodes. In the group with positive nodes, increasing number of positive nodes and involvement of common iliac nodes correlated with decreased survival. A randomized study showed that postoperative chemoradiation improved survival in patients with positive lymph nodes, positive surgical margins, or tumor present in the parametrium.¹¹⁷

Abbreviation: N, number of patients.

Treatment options EBRT

EBRT is used as initial treatment in patients with bulky tumors. The usual plan is to give 40–45 Gy to the whole pelvis. This gives a homogeneous distribution to the central mass plus the regional lymph nodes. Such treatment reduces the primary tumor and any regional lymph nodes harboring disease, and it destroys microscopic foci in lymph-vascular spaces adjacent to the tumor. The shrinkage of the primary tumor allows better dose distribution from intracavitary irradiation.

High-energy photons (15–18 MV) are usually preferred for pelvic treatment because they spare superficial tissues that are unlikely to be involved with tumor. Simulation films, as well as CT, MRI, PET scan, and lymphangiography, guide the radiation oncologist in selecting boundaries for the portals. Typical radiation therapy fields are shown in Figure 16. A standard course of radiation therapy is 40 to 45 Gy given with external beam radiation tberapy (EBRT). Patients with grossly positive pelvic nodes within the 40- to 45-Gy field require a boost with a small field (Figures 16 and 17). The dose to the boost area is 8–10 Gy. The total dose to the positive nodes, including a 1–2 cm margin, is 60–66 Gy, which includes the contributions from brachytherapy intracavitary systems. Intensity-modulated radiation therapy (IMRT) may be used to boost the dose to large pelvic nodes (up to approximately 66 Gy) in a very tightly defined volume.

There has been a recent interest in using IMRT in the treatment of cervical carcinoma. Unlike standard treatment, IMRT allows one to dose paint tissues in the area of treatment, that is, allowing higher doses to tumor, while giving less dose to normal tissues especially small bowel (Figure 17). Mundt et al.¹⁷⁷ have published reports showing a decrease in both acute and chronic¹⁷⁸ bowel toxicities in patients with endometrial or cervical carcinoma treated postoperatively to the pelvis with IMRT compared to standard treatment. However, the highly conformal dose distributions achieved by IMRT also increases the room of error. In particular, great attention needs to be given to internal organs motion (especially the bladder and the rectum) and tumor regression, and therefore at this time IMRT is still considered the investigation therapy, especially in the field of intact cervix. Several multi-institutional trials are underway evaluating the use of IMRT for cervical cancer.

Intracavitary radiation therapy (ICRT)

The importance of ICRT (intracavitary radiation therapy) for cervical cancer should not be underestimated because, although EBRT plays a critical role in sterilizing pelvic wall disease and improving tumor geometry, too much reliance on external beam irradiation will compromise the chance for central disease control and increase the risk of complications.

Brachytherapy is usually delivered using afterloading applicators that are placed in the uterine cavity and vagina. Ideal placement of the intrauterine tandem and vaginal ovoids produces a pear-shaped radiation distribution, delivering a high radiation dose to the cervix and paracervical tissues and a reduced dose to the rectum and bladder. Several systems have been used throughout the world to determine dose rates and doses for cervical cancer. In the United States, the paracentral doses are most frequently expressed at a single point, point A, which is defined earlier. Point A bears no consistent relationship with the tumor or target volume but lies approximately at the crossing of the ureter and uterine artery. Other systems of dose specifications include the International Commission on Radiation Units and Measurements (ICRU) reference points based on ICRU Report 38 (1985) and the mg-h system. Whichever system of dose specification is used, emphasis should always be placed on optimizing the relationship between the intracavitary applicators and the cervical tumor and other pelvic tissues. Source, strength, and position should be carefully chosen to provide optimal tumor coverage with exceeding safe doses to normal tissue (Figure 18).

In the past, clinicians regarded the radiobiological advantages of LDR intracavitary treatment (usually delivery of 40–60 cGy/h to point A) as a major factor contributing to the success of cervical cancer treatment. These LDRs permit repair of sublethal cellular injury, preferentially sparing normal tissues and optimizing the therapeutic ratio. During the past two decades, computer technology has made it possible to deliver brachytherapy at very HDRs (<100 cGy/min) using a high-activity cobalt 60 or iridium 192 source and remote afterloading. HDR intracavitary therapy is now become the standard of care in most parts of the world. Clinicians have found this approach attractive because it does not require that patients be hospitalized and may be more convenient for the patient and the physician. Multiple randomized and nonrandomized studies have suggested that survival rates and complications rates with HDR treatment are similar to those with traditional LDR treatment.¹⁷⁹ In 2012,¹⁸⁰ the American Brachytherapy Society suggested guidelines for the use of HDR brachytherapy for carcinoma of the cervix. The group emphasized the importance of factors that were already considered critical to successful LDR treatment—optimized applicator position, balanced use of external beam therapy and brachytherapy, compact overall treatment duration, and delivery of an adequate dose to tumor while respecting normal tissue tolerance limits.

Image-based brachytherapy is becoming increasingly common, particularly in Europe. Institutions are using MRI-based treatment planning to plan their doses to tumor as well as doses to avoid structures such as the bladder and rectum; however, large prospective studies and careful analysis will be needed before this becoming standard of care.

Patient selection

For patients with IB1 tumors, the choice between surgery and radiation therapy is based primarily on patient preference, anesthetic and surgical risks, physician preference, and understanding of the nature and incidence of complications of radiation therapy and hysterectomy. In general, surgery is often chosen for younger patients in the hope of preserving ovarian function and hopefully reducing vaginal shortening, while radiation therapy is often selected for older postmenopausal women to avoid the morbidity of a major surgical procedure. Patients with stage IB2 disease can be treated with either surgery followed by radiation therapy or definitive radiation therapy. The biases are so large that the Gynecologic Oncology Group (GOG) could not complete trial randomizing patients with stage IB2 disease between surgery followed by chemoradiation therapy and definitive radiation therapy. Radiation therapy is the primary local therapy for most patients with stage IIB-IVA disease.

Outcomes

Complications

CIS and stage IA1 disease

Treatment of HGSILs is rapidly changing. LEEP is one effective therapy for HGSILs. Other techniques such as cryosurgery and laser ablation have also proven effective. Regardless of the technique used, HGSILs should be entirely visible by colposcopy, the entire transformation zone should be visualized, and the ECC specimen should be negative. Conization with a knife is preferred when the ECC specimen is positive. All margins must be clear of intraepithelial lesions.

Stage IA1 (microinvasive) squamous cell carcinomas that invade the stroma <3 mm and have no LVSI are usually not visible to the unaided eye, and cytology is abnormal. The diagnosis requires cone biopsy, which yields a specimen adequate for diagnostic purposes. Conization alone is also potentially a low-risk therapy for patients who wish to retain fertility and who have invasion <3 mm in depth with no LVSI. It is important to remember that the margins of a cone specimen must be negative. When the conization specimen has a positive margin, a second tissue specimen must be obtained because foci of frankly invasive carcinoma may lie adjacent to the positive margin. Patients should be informed that the conservative approach carries a small risk. There is very little current information on which to base a recommendation regarding the use of conization as therapy for women with nonsquamous cervical cancers.¹⁵⁵ Patients who elect conization therapy must be willing to be monitored closely for the development of residual or recurrent cervical neoplasia.

The most conventional treatment of stage IA1 disease is a type 1 (simple extrafascial) hysterectomy. If the patient is young, the ovaries are left in place. Patients can also be treated with radiation therapy alone, usually consisting of intracavitary therapy alone. The 10-year disease control rate with radiation therapy alone is 95–100%.¹⁹⁴

Stage IA2 disease

Small lesions that invade 3–5 mm have an average risk of lymph node metastasis of about 5%. The standard treatment of patients with this stage of disease is type II (modified radical) hysterectomy and pelvic node dissection.

Recently, a number of studies have explored less radical surgical options for early-stage cervical cancer, including simple hysterectomy, simple hysterectomy, simple trachelectomy, and cervical conization with or without sentinel lymph node biopsy and pelvic lymph node dissections especially in patients who wish to preserve fertility. Such options may be available for patients with low-risk early-stage cervical cancer including patients with any histology except neuroendocrine tumor, tumor size <2 cm, stromal invasion <10 mm, and no LVSI. Presently, three international trials are underway looking at this option for patients with early-stage disease.

If surgery is contraindicated, these patients can be treated with radiation alone, usually with pelvic radiation therapy plus brachytherapy. However, in special situations, brachytherapy alone may be sufficient in controlling disease.

Stage IB1 and small-stage IIA disease

Treatment of invasive carcinoma or carcinoma of FIGO stage IB or greater is determined on the basis of tumor size and the presence or absence of lymph node metastases (Figure 5).

Stage IB1 tumors, which are <4 cm in size, are considered small; however, they are associated with a significant risk of microscopic paracervical extension or lymph node metastasis. In a prospective study in patients treated with radical hysterectomy who had clinically estimated maximum tumor diameter <3 cm, the GOG reported that 16% of the patients (42 of 261) had lymph node metastases.¹⁹⁵ Landoni et al.¹⁶³ found a 25% incidence of positive nodes (28 of 114 patients) in patients treated with radical hysterectomy for stage IB-IIA tumors that measured 4 cm or less on initial clinical examination. Therefore, for patients with stage IB1 or small IIA (<4 cm diameter) disease, the treatment is either type III (radical) hysterectomy plus bilateral pelvic lymphadenectomy or radical radiation therapy. The goal of both of these treatment options is to destroy malignant cells in the cervix, paracervical tissues, and regional lymph nodes.

OS rates for patients with stage IB1 or small IIA disease treated with either surgery or radiation therapy are usually in the range 80–90%, suggesting that the two treatments are equally effective. However, only one prospective randomized trial has compared the two treatments directly.¹⁶³ There were no significant differences in the rates of relapse or survival between the two arms, but the overall rate of grade 2 and 3 complications was greater for patients treated with hysterectomy. Therefore, for patients with stage IB1, the choice of treatment is based on patient preference, anesthetic and surgical risks, physician preference, and an understanding of the nature and incidence of complication with radiation therapy and hysterectomy. The role of pelvic radiation therapy after radical hysterectomy is still being defined. The GOG, in a prospective trial, randomized patients with intermediate risk of recurrence after radical hysterectomy for stage IB carcinoma to pelvic irradiation or no further treatment.¹⁹⁶ The preliminary analysis showed a 47% reduction in the risk of recurrence when postoperative irradiation was given (15% vs 28%, p = 0.008). An update of this study published in 2006 showed a statistically reduction in the risk of recurrence and PFS however no statistical difference in OS with the addition of postoperative radiation therapy. The conclusion by the authors was that pelvic radiotherapy after radical surgery significantly reduced the risk of recurrence and prolongs PFS in women with stage IB cervical cancer, particularly in patients with adenocarcinoma or adenosquamous histologies.¹⁹⁷ The Southwest Oncology Group reported the results of a randomized trial of patients treated with radical hysterectomy followed by radiation therapy versus radiation therapy plus cisplatin-based chemotherapy in patients with high risk factors including pelvic lymph node metastases, parametrial involvement, and or positive margins. The authors found that patients who received radiation therapy plus chemotherapy had a significant improvement in survival compared with the survival of patients treated with radiation alone.¹¹⁷

Stage IB2 disease

Patients with tumors >4 cm in diameter whose para-aortic lymph nodes are found to be free of disease have excellent survival rates when treated with whole-pelvis EBRT plus brachytherapy. However, these tumors appear on clinical examination to be technically resectable, and the ideal management of these tumors is a subject of considerable controversy. The approach to these tumors differs widely between centers, and the biases are so large that the GOG closed a trial early owing to a lack of accrual that compared surgery plus chemoradiation versus chemoradiation alone.

Although radiation therapy is effective for many patients with stage IB2 disease, central disease recurrences occur in at least 8–10% of patients with bulky endocervical cancers.^{167, 183, 184} The literature contains numerous reports on the use of an adjunctive hysterectomy for patients with bulky endocervical carcinomas treated with primary radiation therapy. However, in 1999, the GOG concluded from a study that evaluated adjunctive hysterectomy, that adjunctive hysterectomy did not improve local control or survival but did increase toxicity when added to chemoradiation therapy in patients with stage IB2 disease.¹⁸⁵

Several investigators recommend treating these tumors with initial surgery followed by postoperative radiation therapy or chemoradiation depending on the pathology findings. In a randomized trial by Landoni et al.,¹⁶³ patients with stage IB2 tumors were randomized to initial surgery versus definitive radiation therapy. In this trial, even though the survival was similar in both arms, 84% of the patients treated with initial surgery required postoperative radiation therapy, which contributed to a higher complication rate in that arm.

Several trials have been initiated to study the role of induction chemotherapy before surgical exploration in patients with bulky lesions who would otherwise be poor candidates for radical hysterectomy.^{198, 199} A meta-analysis²⁰⁰ collected individual patient data (IPD) from 21 randomized trials of neoadjuvant chemotherapy in locally advanced cervical cancer. This analysis included data from comparison of the benefits of neoadjuvant chemotherapy followed by radical radiotherapy versus radical radiotherapy alone (2074) and for comparison of neoadjuvant chemotherapy followed by surgery (±radiotherapy) versus radical radiotherapy alone (872 patients). They found that the group of trials using cycles lasting longer than 14 days showed a significant 25% increase in the relative risk of death with neoadjuvant chemotherapy, representing an absolute 8% reduction in 5-year survival compared to shorter chemotherapy cycle lengths, where there was a significant 17% decrease in the relative risk of death, representing an absolute improvement in 5-year survival of 7%. They also found a significant 35% increase in the risk of death for trials that used <25 mg/m² cisplatin per week, reducing absolute 5-year survival by 11%; however, the results for the higher dose-intensity group were less clear, with only a trend toward increased survival. The second comparison of patients treated with neoadjuvant chemotherapy and surgery versus radiation therapy only showed that patients treated with neoadjuvant chemotherapy had a highly significant 35% reduction in the risk of death (p = 0.0004) that translated into a 14% absolute increase in 5-year OS.²⁰¹ Unfortunately, this meta-analysis only included trials before 1999, when radiotherapy alone was still the standard treatment. Ultimately, however, this approach may need to be compared with optimized chemoradiation to determine the most effective, least toxic therapy for these patients. The EORTC (European Organisation for Research and Treatment of Cancer) completed a trial addressing this specific question. Patients with IB2 cancers are being randomized to neoadjuvant chemotherapy followed by radiation or current chemotherapy and radiation.

Two prospective randomized trials^{185, 186} indicate that patients who are treated with radiation for bulky central disease benefit from concurrent administration of cisplatin-containing chemotherapy. A third study suggests that patients who require postoperative radiotherapy because of findings of lymph node metastasis or involved surgical margins also benefit from concurrent chemoradiation.¹¹⁷ These studies are discussed in more detail in the section titled “Concurrent Chemoradiation,” later in this chapter.

Stage IIB-IVA disease

Radiation therapy is the primary local treatment of most patients with locoregionally advanced (stages IIIB-IVA) cervical carcinoma. The success of treatment depends on a careful balance between EBRT and brachytherapy that optimizes the dose to tumor and normal tissues and on the overall duration of treatment. In the French Cooperative Group study of 1875 patients treated with radiation therapy according to Fletcher guidelines, Barillot et al.¹¹² reported 5-year survival rates of 70%, 45%, and 10% for patients with stage IIB, IIIB, and IVA tumors, respectively.

Local and distant disease recurrences continue to be a problem for patients with locally advanced disease. Neoadjuvant chemotherapy has produced excellent tumor responses; however, randomized trials have failed to demonstrate improvements in survival. Other approaches that have been used to try to improve outcome in these patients, including neutrons, hyperbaric oxygen, and hypoxic cell sensitizers, have also produced disappointing results.

Concurrent chemoradiation

In 1999, five prospective randomized trials, involving patients with locoregionally advanced cervical cancer,^{117, 185, 186, 188, 189} provided compelling evidence that the addition of concurrent cisplatin-containing chemotherapy to standard radiotherapy reduces the risk of disease recurrence by as much as 50% and thereby improves the rates of pelvic disease control and survival (Table 6).

Abbreviations: CI, confidence interval; FU, follow-up; HU, hydroxyurea; PA, para-aortic; RT, radiotherapy.

Results from prospective randomized trials that investigate the role of concurrent radiotherapy and cisplatin-containing chemotherapy for patients with locoregionally advanced cervical cancer.

^a Patients in control arm had prophylactic para-aortic irradiation.

^b All patients had extrafascial hysterectomy after radiotherapy.

^c Survival.

^d Chemotherapy was begun on day 1 and continued every 4 weeks throughout and after radiation therapy.

^e This study had four arms: arm 1, conventional radiation therapy (RT); arm 2, conventional RT with adjuvant chemotherapy consisting of 5-FU orally at 200 mg/day given for 3 courses of 4 weeks, with a 2-week rest every 6 weeks; arm 3, conventional RT with concurrent chemotherapy; and arm 4, conventional RT with concurrent and adjuvant chemotherapy. The addition of adjuvant therapy did not affect recurrence, but there was a significant difference in the recurrence rate between the conventional RT and the conventional RT plus concurrent chemotherapy arms.

In two studies,^{188, 189} the GOG randomly assigned patients with stages IIB-IVA disease to receive either hydroxyurea or cisplatin-containing chemotherapy during external beam irradiation. All three of the cisplatin-containing regimens in these trials produced local control and survival rates superior to those for the control (hydroxyurea and radiation). In a third study,¹⁸⁵ patients with stage IB tumors measuring at least 4 cm in diameter were randomly assigned to receive radiation alone or radiation plus weekly cisplatin before an extrafascial hysterectomy. Patients who received cisplatin were more likely to have a complete histologic response and were more likely to be disease free at the time of preliminary analysis. A fourth study,¹¹⁷ sponsored by the Southwest Oncology Group and the GOG, randomized patients after a radical hysterectomy pelvic radiation therapy or pelvic radiation therapy plus chemotherapy if they had high risk factors. The trial found improvement of survival of chemotherapy and radiation therapy compared to radiation therapy alone at 5 years; however, the benefit of the chemotherapy to the radiation therapy in a univariate analysis was less significant in tumors size <2 cm and patients with only one node positive.²⁰⁵ The absolute improvement in 5-year survival for adjuvant chemotherapy in patients with tumors ≤2 cm was only 5% (77% vs 82%), while for those with tumors >2 cm, it was 19% (58% vs 77%). Similarly, the absolute 5-year survival benefit was less evident among patients with one nodal metastasis (79% vs 83%) than when at least two nodes were positive (55% vs 75%).²⁰⁵

During the same interval, the Radiation Therapy Oncology Group (RTOG)¹⁸⁶ conducted a trial in which radiotherapy alone was compared with pelvic irradiation (including prophylactic para-aortic irradiation) plus concurrent cisplatin and 5-FU. This study demonstrated a significant improvement in outcome for patients with stages III or IV disease as well as for patients with stages IB2 or II cervical cancer with concurrent chemotherapy.¹⁹⁴ An update of this trial, with a median follow-up period of 6.6 years for the surviving patients,²⁰⁶ reported that the OS rate for patients treated with chemotherapy and radiation therapy compared to radiation therapy was still significantly better (67% vs 41% at 8 years, p = < 0.0001) and the conclusion by the authors was that chemotherapy with radiation therapy significantly improved the survival rate of women with locally advanced cervical cancer without increasing the rate of late treatment-related side effects.²⁰⁶ Only one large randomized trial has failed to demonstrate a significant advantage from concurrent cisplatin-based chemotherapy in cervical cancer patients. Pearcey et al.²⁰² published this trial in 2002. The authors suggest that difference in technique could explain the difference between their results and the results of the five earlier trials, although the survival rate in their control arm indicated that the margin for improvement was smaller than that in the earlier trials. This trial was also the smallest of the six trials.

Taken together, the randomized trials provide strong evidence that the addition of concurrent cisplatin-containing chemotherapy to pelvic radiotherapy benefits selected patients with locally advanced cervical cancer. It remains to be resolved whether or not 5-FU plays a significant role. The combination of cisplatin plus FU was tested in four of the trials [RTOG 90-01, GOG 85, GOG 120, and Southwest Oncology Group (SWOG) 8797]. In GOG 120, the frequency of grade 3 and 4 leukopenia was significantly higher in the arm with cisplatin/5-FU and hydroxyurea compared to the arm with cisplatin and hydroxyurea alone, with equal effectiveness. Therefore, it was felt that cisplatin alone was equally effective as cisplatin-5-FU and less toxic, although there has been no adequately powered direct randomized comparison of these two regimens without hydroxyurea.

A meta-analysis of 18 trials²⁰⁷ with concurrent chemotherapy and radiation (4580 patients) in patients with cervical cancer concluded that concomitant chemotherapy and radiotherapy improved overall and PFS and reduced local and distant recurrence in selected patients with cervical cancer. Concomitant chemotherapy and radiation therapy produced a 12% absolute increase in survival with greater evidence of benefit in the trials using platinum-based chemotherapy than in those with nonplatinum-based chemotherapy.²⁰⁷ More recently, a systematic review and meta-analysis based on IPD²⁰⁸has documented a 7% absolute improvement in 5-year survival. The benefits were similar in the trials using platinum and nonplatinum chemoradiotherapy.²⁰⁸ In this analysis, there is a suggestion that the magnitude of benefit with chemoradiotherapy varies according to stage, but not to other patients characteristics, suggesting a greater benefit in patients with early-stage disease compared to stage III and IV disease.²⁰⁸

In 2012, Duenas-Gonzales published a large phase III study that randomized patients with locally advanced cervical cancer to cisplatin plus radiation versus cisplatin plus gemcitabine and radiation therapy.²⁰⁹ Women assigned to treatment with the combination regimen also received additional systemic therapy after chemoradiation was complete. With a median follow-up of 3 years, women who received cisplatin plus gemcitabine had a 32% reduction in disease progression and a higher rate of PFS at 3 years compared with those treated with cisplatin alone (74% vs 65%, respectively). In addition, cisplatin plus gemcitabine resulted in a 32% survival advantage. However, there were methodological problems with follow-up in this study and a second publication by the authors purported no benefit in various subgroups.²¹⁰ Despite these results, there are reports from other investigators that the combination of cisplatin, gemcitabine, and pelvic irradiation results in unacceptable toxicity²¹¹ and presently is not commonly used in the United States.

These studies raise other interesting questions that will undoubtedly be the subjects of future studies. Although North American studies have emphasized cisplatin-containing regimens, investigators in Southeast Asia have reported improved outcome when radiation was combined with epirubicin²⁰³ or mitomycin and 5-FU.²⁰⁴ Other drugs that are being studied for their radiosensitizing effects in patients with advanced disease are paclitaxel,²¹² carboplatin,²¹³ nedaplatin,²¹⁴ topotecan,²¹⁵ and multiple biologic response modifiers. RTOG just published results of a phase II study evaluating the combination of bevacizumab with cisplatin in combination with radiation therapy and found results that were promising with 3-years OS, DFS, and LRF of 81.3%, 68.7%, and 23.3%, respectively, in 49 patients.²¹⁶ Another potential pathway is the inhibition of ribonucleotide reductase (RNR). Elevated RNR levels are associated with an increased risk of an incomplete response to chemoradiation and an increased risk of disease recurrence.²¹⁷ Therefore, targets that inhibit RNR may be of potential value in combination with RT. One such agent, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone, has been evaluated in a single-institution phase 2 trial and with a median follow-up of 20 months; clinical responses were observed in 24 of 25 patients with suggested metabolic complete responses noted in 23 of 24 patients evaluated by PET/CT at 3 months.²¹⁸ These encouraging results have prompted a larger, multi-institutional, randomized phase II study as well as a possible phase III through NRG. Other potential targets/pathways that are being investigated include EGFR expression and inhibition of poly (adenosine diphosphate-ribose) polymerase (PARP).

Para-aortic metastasis

Metastatic cancer in the para-aortic lymph nodes can be confirmed with fine-needle aspiration, laparoscopy, or extra-peritoneal laparotomy. Laparoscopy and laparotomy, using the extra-peritoneal approach, allows the removal of positive nodes and sampling of other para-aortic nodes, which may enhance control with radiation therapy and help design the treatment field.

The superior boundary of the extended EBRT portal provides a margin of 3 cm above the most cephalad of the positive nodes. The superior boundary limit is the T12 vertebra. Currently, patients with positive pelvic nodes or low common iliac nodes may have the field extended to the L1–L2 interspace.

Patients with para-aortic lymph node involvement can be treated effectively with extended-field irradiation. Five-year survival rates range from 25% to 50%.^{219, 220} The value of prophylactic extended-field irradiation was tested in two randomized trials and both trials found no advantage in the use of prophylactic para-aortic radiation.^{221, 222}

The role of concurrent chemotherapy with extended-field irradiation has been evaluated in several phase II studies.²²³ Although, side effects are greater when treatment fields are enlarged, combined therapy may be tolerable if careful consideration is given to the chemotherapy regimen, volume of tissue irradiated, and other factors that might increase the risk of serious toxicity. In conclusion, it is tempting to extrapolate from the results achieved with combinations of pelvic radiation and chemotherapy; however, patients need to be informed that the cost-benefit ratio of concurrent chemotherapy and extended-field irradiation has not been formally tested but this is where IMRT may be a benefit in reducing acute toxicity.

Unsuspected invasive cancer discovered after simple hysterectomy

Sometimes the pathologist discovers unsuspected invasive cervical carcinoma in the tissue specimen in patients who undergo hysterectomy for what is presumed to be a benign pelvic condition. Many factors can lead to such an event.²²⁴

Patients with unsuspected invasive cervical carcinoma detected after simple hysterectomy have been classified in five groups according to the amount of disease and presentation: (1) microinvasive cancer, (2) tumor confined to the cervix with negative surgical margins, (3) positive surgical margins but no gross residual tumor, (4) gross residual tumor by clinical examination documented by biopsy, and (5) patients referred for treatment more than 6 months after hysterectomy (usually for recurrent disease).²²⁵ The therapy plan is based on the amount of residual disease. Patients with minimal invasion and no residual disease require at most brachytherapy to the vaginal apex; patients with gross disease at the specimen margin require full-intensity therapy. Patients with minimal or no known gross residual disease (groups 1–3) have excellent 5-year survival rates (59–79%), whereas rates for patients with gross residual disease (groups 4 and 5) are poorer (in the range of only 41%).²²⁶

Recurrent disease

Pelvic exenteration

Pelvic exenteration is a potentially curative procedure for patients who, following radiation therapy, have a central pelvic recurrence or a new primary tumor in the irradiated field.^231–233 Advances in surgical technique, anesthesia, and postoperative care have decreased intraoperative and postoperative complications, and thus have greatly reduced operative mortality.^{224, 232, 233} Advances in ostomy appliances and care have given patients the opportunity to live a nearly normal life and to be able to meet their personal needs and responsibilities after surgery. The type of exenteration is determined by the anatomical site of the cancer (Figure 19).

Treatment of stage IVB or recurrent disease

Chemotherapy

Single-agent chemotherapy

Using chemotherapy to treat metastatic or recurrent carcinoma of the cervix is relatively ineffective. Median survival ranges between 4 and 8 months. The most active single agents include cisplatin, paclitaxel, topotecan, vinorelbine, and ifosfamide. Cisplatin is regarded as the most active agent in cancer of the cervix. The response rate (RR) is 17–21%.^{235, 236} Doses used range from 50 to 100 mg/m². Bonomi and colleagues compared 50–100 mg/m² and noted that the higher dose was associated with a better partial RR (31% vs 21%) and a slightly better complete RR (13% vs 10%). Response duration, PFS, and survival measures failed to improve with the higher dose.²³⁶ Carboplatin given at 340–400 mg/m² every 28 days to 175 patients induced a complete response in 10 (5.7%).²³⁷ The total RR for carboplatin from a number of studies is 19%.

Paclitaxel has consistently demonstrated clinical activity, even in patients who received prior platin therapy with RRs of 17–31% and median survival of about 7 months, including those patients with nonsquamous histology. The other three—topotecan, vinorelbine, and ifosfamide^238–240—have also shown substantial responses and are being used in combination therapy in phases II and III trials.

Combination chemotherapy

Nineteen single agents have activity against cervical cancer, defined as the ability to induce a 15% RR when used as a single-agent (Table 7), but survival rates have not been improved by adding other drugs to cisplatin. Numerous reports describe a higher RR with combination therapies accompanied by an increase in toxicity. Ifosfamide has received the most interest until recently. Several small phase II studies evaluated treatment with combinations of ifosfamide and either cisplatin or carboplatin in patients who had not received radiotherapy. RRs for these combinations ranged between 50% and 62%.^241–244

Agent	Response (%)
Alkylating agents
Cyclophosphamide	38/251 (15)
Chlorambucil	11/44 (25)
Melphalan	4/20 (20)
Ifosfamide	35/157 (22)
Mitolactol	16/55 (29)
Heavy metal complexes
Cisplatin	190/815 (23)
Carboplatin	27/175 (15)
Antitumor antibiotics
Doxorubicin	45/266 (17)
Bleomycin	19/176 (11)
Mitomycin	5/23 (22)
Antimetabolites
Fluorouracil	29/142 (20)
Methotrexate	17/96 (18)
Hydroxyurea	0/14 (0)
Plant alkaloids
Vincristine	10/55 (18)
Vinblastine	2/20 (10)
Etoposide	0/31 (0)
Miscellaneous agents
Altretamine	12/64 (19)
Irinotecan (CPT-11)	36/192 (19)
Paclitaxel	14/74 (19)
Docetaxel	1/13 (8)
Topotecan	8/43 (19)
Hexamethylmelamine	12/64 (19)
Razoxane	5/28 (18)

Source: Data from Refs 235–240.

Combinations of cisplatin and continuous infusion 5-FU,^245–247 cisplatin and paclitaxel,^{248, 249} cisplatin and vinorelbine,²⁵⁰ and cisplatin and gemcitabine^{251, 252} also produce high response in previously untreated patients. The combination of carboplatin and liposomal doxorubicin has shown modest activity in this clinical setting.²⁵³ Again, RRs decrease significantly if patients have had previous irradiation.^{246, 252}

A GOG-randomized phase III trial reported that combining topotecan with cisplatin had a better RR than cisplatin alone.²⁵⁴ The RR was 13% in the cisplatin arm and 27% in the combination arm. There was also an improvement in median survival by 3 months as well as a slight improvement in quality of life as determined by the functional assessment of cancer therapy-cervical (FACT-CX). They found the previous radiosensitizing chemotherapy and interval from diagnosis predicted for response. Response was more frequent in nonirradiated sites (70% vs 23%). This has led the GOG to their next prospective trial for primary stage IVB or recurrent/persistent carcinoma of the cervix. In this trial, patients were randomized between four arms: arm 1, paclitaxel and cisplatin (PC); arm 2, vinorelbine and cisplatin (VC); arm 3, gemcitabine and cisplatin (GC); and arm 4, topotecan and cisplatin (TC). This study was closed early due to futility. However, in 513 patients, VC, GC, or TC was not superior to PC in terms of OS, but the trend in RR, PFS, and OS favored PC.²⁵⁵ In a separate report, health-related quality of life outcomes for this study showed no difference between the four arms except that PC had a higher rate of neuropathy, but the final conclusion was that PC should be the standard of care for recurrent or metastatic cervical cancer.²⁵⁶

Recently, however, a major step forward in the treatment of patients with recurrent or metastatic cervical cancer was achieved with the result of GOG 240, which randomly assigned patients to treatment with 1 of 2 chemotherapy regimens (cisplatin plus paclitaxel vs paclitaxel plus topotecan) and to bevacizumab versus no bevacizumab.²⁵⁷ There was no difference in outcomes noted between the chemotherapy regimens. However, when compared with chemotherapy alone, the addition of bevacizumab significantly improved OS (17 months vs 13.3 months), PFS (8.2 months vs 5.9 months), and RR (48% vs 36%) without a significant deterioration in health-related quality of life.²⁵⁸ Major treatment-related toxicities included fistula (3%), thromboembolism (8%), and easily managed hypertension (25%).²⁵⁸ Since this publication, cisplatin-paclitaxel-bevacizumab triplet has been listed as Category 2A in the National comprehensive Cancer Network (NCCN) Clinical Practice Guidelines for Cervical Cancer.²⁵⁹

Despite the result of GOG 240, the prognosis of patients with recurrent or metastatic cervical cancer remains poor and represents an urgent unmet need worldwide. Therefore, better alternatives need to be explored including determining prognostic factors, administration of novel agents that may improve the therapeutic index of definitive chemoradiation and various immunotherapeutic approaches. Moore et al.²⁶⁰ evaluated 428 patients enrolled in three GOG trials and determined 5 prognostic factors including race, performance status, pelvic disease, prior radiosensitizer, and time interval from diagnosis to the first recurrence <1 years, that may have utility in clinical practice to identify women who are not likely to respond to standard cisplatin-based regimens and that may benefit from investigational trials.

The rationale for immunotherapy in cervical cancer is based on the causative role of HPV infection in the disease. HPV infection invokes cellular immune response, and regulatory T cells appear to play a role in local immune suppression in HPV-associated tumors. New agents that interrupt the mechanisms involved in cancer immune evasion have soon promising results. Basu presented final results of a randomized phase II trial involving 110 women from India with recurrent/refractory cervical cancer who were randomized to receive live attenuated Listeria monocytogenes vaccine with or without cisplatin at the 2014 Annual Meeting of the American Society of Clinical Oncology.²⁶¹ The final 12-month OS was 36% and 18 month OS was 28%.²⁶¹ The overall RR was 11% and included 6 complete responders and 6 partial responders. ³²¹The addition of cisplatin did not significantly improve OS or RR.²⁶¹ These promising results have led to a trial in the United States using the same live-attenuated vaccine under the auspices of the NRG (GOG 265/NCT01266460).

Other pathways including regulatory pathways that limit the immune response to cancer including the upregulation of cytotoxic T lymphocyte-associated molecule-4 (CTLA-4) and PD-1 are increasing being well characterized. In addition, the role of adoptive immunotherapy using tumor-infiltrating lymphocytes represents another potential useful approach for patients with advanced or metastatic disease. In this technology, the tumor is excised and enriched for tumor-infiltrating lymphocytes, which are expanded after selection and reinfused to patients after lymphodepletion. On the basis of the responses noted in tumors such as malignant melanoma, this approach is being evaluated in an ongoing trial at the NCI for patients with recurrent or refractory metastatic cervical cancer (NCT01266460).

Signaling pathways affected by HPV are also an area where novel targeted drugs may be a benefit in the fight against cervical cancer. Genomic data have documented KRAS and P13KCA mutations and are now awaiting proof of concept by demonstration that these pathways are both turned on and necessary for the cervical cancer success. Endpoints including showing purposeful activations of MEK/ERK and AKT proliferation, invasion and survival pathways would provide justification for testing active agents targeting these pathways. Potential new agents include cetuximab, gefitinib, erlotinib, and selumetinib. Irradiation is a major cause of DNA damage. Therefore, inhibition of PARP provides another potential target for the treatment of cervical cancer. Two trials currently are being conducted among patients with cervical cancer through NRG (GOG 127W/NCT0101266447and GOG76HH/NCT01282852).

Summary

In patients with recurrent cervical cancer, it is important first to determine if the patient is a candidate for definitive surgery or radiation therapy. Five-year survival rates range from 20% to 50% if one of these therapies can be administered. Systemic chemotherapy can be used for treatment of both recurrent and metastatic disease, but careful attention should be paid to balancing benefit and toxicity. Further research is needed to determine the impact of chemotherapy on quality of life and the sensitivity to chemotherapy of patients who received prior chemotherapy as part of chemoradiation therapy as well as the importance of biological and immunotherapy agents. The key to success will be the transportation of success seen in the developing countries to success in areas of the world where advanced-stage invasive cervical cancer is most common.

---

Only gold members can continue reading. Log In or Register to continue

Share this:

• Click to share on Twitter (Opens in new window)
• Click to share on Facebook (Opens in new window)

Related

Related posts:

Aberrant signaling pathways in cancer Disparities in cancer care Monoclonal serotherapy Neoplasms in acquired immunodeficiency syndrome Chemical carcinogenesis Skeletal complications

Stay updated, free articles. Join our Telegram channel

Join