Neville F. Hacker
Michael L Friedlander
Cervical cancer is the second most common cancer in women worldwide and the most common female cancer in many developing countries. Annual global estimates for the year 2000 were 470,600 new cases and 233,400 deaths (1). Both the incidence and mortality rates are likely to be underestimated in underresourced countries because of poor registry reporting. In the United States, 11,270 new cases with 4,070 deaths were anticipated in 2009 (2).
The mean age for cervical cancer is 51.4 years, with the number of patients fairly evenly divided between the age groups 30 to 39 and 60 to 69 years (1). There is a trend toward increasing stage with increasing age, suggesting that older patients are not being screened as often as younger patients (1).
In recent years, molecular biology has firmly established a causal relationship between persistent infection with high-risk human papilloma virus (HPV) genotypes and cervical cancer. In a study of almost 1,000 cases of cervical cancer worldwide, the prevalence of HPV infection was 99.7% (3). This causal relationship has led to the promise of global cervical cancer prevention using both primary prevention through vaccination against HPV in young women and secondary prevention by screening directly for carcinogenic HPV in older women (4). Two HPV vaccines are currently approved by the FDA: the quadrivalent Gardasil and the bivalent Cervarix.
Cervical cancer progresses slowly from preinvasive cervical intraepithelial neoplasia (CIN) to invasive cancer, and screening asymptomatic women with regular Papanicolaou (Pap) smears allows diagnosis of the readily treatable preinvasive phase. Hence, appropriate screening programs are an important public health issue. In developed countries, most cases of cervical cancer occur in women who have not had regular Pap smear screening.
In low-resource countries, facilities for screening asymptomatic women are not readily available, and cultural attitudes and lack of public education also discourage early diagnosis. Hence, most patients in developing countries present with advanced disease that may have already eroded into the bladder, rectum, pelvic nerves, or bone. Because radiation therapy and palliative care facilities are also usually inadequate in these countries, many of these women die as social outcasts, with severe pain and a foul-smelling vaginal discharge. Most of these women have dependent children, so the social devastation caused by this disease can be readily appreciated.
Even in the United States, nearly 9% of women receive no therapy for their disease (5). Trimble et al. reported that this was particularly common in older, unmarried women, who presented with late-stage disease. Obstacles to treatment were postulated to include lack of access to treatment facilities, inability to pay, and inadequate social support.
Early diagnosis of cervical cancer can be extremely challenging because of three factors:
Abnormal vaginal bleeding is the most common presenting symptom of invasive cancer of the cervix. In sexually active women, this usually includes postcoital bleeding, but there may also be intermenstrual or postmenopausal bleeding. Unlike endometrial cancer, which usually bleeds early, cervical cancer often is asymptomatic until quite advanced in women who are not sexually active. Large tumors commonly become infected, and a vaginal discharge, sometimes malodorous, may occur before the onset of bleeding. In very advanced cases, pelvic pain, pressure symptoms pertaining to the bowel or bladder, and occasionally vaginal passage of urine or feces may be presenting symptoms.
In a review of 81 patients diagnosed with cervical cancer in southern California, Pretorius et al. (6) reported that 56% presented with abnormal vaginal bleeding, 28% with an abnormal Pap smear, 9% with pain, 4% with vaginal discharge, and 4% with other symptoms. Patients presenting with an abnormal Pap smear had smaller tumors and earlier-stage disease.
The presence of malignant cells in a background of necrotic debris, blood, and inflammatory cells is typical of invasive carcinoma (Fig. 9.1). Differentiation between squamous and glandular cells is usually possible except for poorly differentiated lesions. The false negative rate for Pap smears in the presence of invasive cancer is up to 50%, so a negative Pap smear should never be relied on in a symptomatic patient (7).
Figure 9.1 Pap smear of cervical squamous cell carcinoma. Malignant squamous cells, singly and in groups, show nuclear pleomorphism. A “tadpole” cell is present on the left. (Original magnification 165×.)
Physical examination should include palpation of the liver, supraclavicular, and groin nodes to exclude metastatic disease. On speculum examination, the primary lesion may be exophytic, endophytic, ulcerative, or polypoid. If the tumor arises beneath the epithelium or in the endocervical canal, the ectocervix may appear macroscopically normal. Direct extension to the vagina is usually grossly apparent, but the infiltration may be subepithelial and suspected only on the basis of obliteration of the vaginal fornices or the presence of apical stenosis. In the latter situation, it may be difficult to visualize the cervix. On palpation, the cervix is firm (except during pregnancy) and usually expanded. The size of the cervix is best determined by rectal examination, which is also necessary for the detection of any extension of disease into the parametrium.
Any obvious tumor growth or ulceration should undergo office punch biopsy or diathermy loop excision for histologic confirmation. Any cervix that is unusually firm or expanded should also undergo biopsy and endocervical curettage (ECC).
If the patient has a normal-appearing cervix but is symptomatic or has an abnormal Pap smear, then colposcopy should be performed. If a definitive diagnosis of invasive cancer cannot be made on the basis of an office biopsy, then diagnostic conization may be necessary.
Colposcopy for Invasive Cancer
Colposcopic detection of a microinvasive carcinoma depends on its size and location. Very small lesions may be missed, although the likelihood of having early stromal invasion increases with the surface extent of the preinvasive lesion (8). If the microinvasive carcinoma is entirely within the endocervical canal, then the ectocervix may be colposcopically normal.
Ectocervical microcarcinomas are classically associated with atypical vessels, which are prone to bleed. Atypical vessels show a completely irregular and haphazard disposition, great variation in caliber, and abrupt changes in direction, often forming acute angles (Fig. 9.2). The intercapillary distance is increased and tends to be variable (8).
Frankly invasive cancers can usually be seen with the naked eye, but the colposcope highlights their surface irregularity and highly atypical blood vessels (Fig. 9.3). Endophytic tumors may present as an “erosion,” the true nature of which can be recognized only by their papillary surface and atypical vessels. Akeratotic surface may mask the colposcopic features of an endophytic lesion, so biopsy of areas of keratosis is mandatory.
Figure 9.2 Colposcopic appearance of microinvasive cervical cancer. Note the severe varicose vascular abnormality with course punctation and transitional forms to atypical vessels.
Figure 9.3 Colposcopic appearance of invasive cervical cancer. Note the surface irregularity and dilated atypical vessels.
Adenocarcinomas present no specific features. They often occur in association with squamous CIN, and all of the vascular changes described previously may be seen with these lesions.
Cervical cancer is staged clinically because most patients worldwide are treated only with radiation therapy.
The 1994 staging system of the International Federation of Gynecology and Obstetrics (FIGO) is shown in Table 9.1 (9). For updated FIGO surgical staging tables (2008), see table 9.1A on page 665. A comparison of the FIGO staging and the TNM (tumor, nodes, metastasis) classification is shown in Table 9.2.
Clinical staging is often inaccurate in defining the extent of disease. The Gynecologic Oncology Group (GOG) (10), in a study of 290 patients with surgically staged cervical cancer, reported errors in FIGO clinical staging ranging from 24% in stage IB to 67% for stage IVA disease. Most patients were upstaged on the basis of surgical exploration, with the most likely sites of occult metastases being the pelvic and paraaortic lymph nodes. Other sites of occult disease were the parametrium, peritoneum, and omentum. As many as 14% of patients may also be downstaged (11), usually because a benign pathologic process is discovered, such as pelvic inflammatory disease, endometriosis, or fibroids.
Noninvasive Diagnostic Studies
Because information about the extent of disease is critical for treatment planning, various imaging studies have been used to define more accurately the extent of disease.
Computed Tomography Computed tomography (CT) has been used to help stage pelvic cancers since the mid 1970s. In addition to the lymph nodes, a pelvic and abdominal CT scan allows an evaluation of the liver, urinary tract, and bony structures. A CT can detect only changes in the size of the nodes, those greater than 1 cm in diameter usually being considered positive. Normal-sized nodes containing microscopic deposits give false negative results, whereas nodal enlargement from inflammatory or hyperplastic changes gives false positive results. If nodes greater than 1.5 cm in diameter are considered positive, then the sensitivity of the test is improved at the expense of the specificity.
Table 9.1 Carcinoma of the Cervix Uteri: FIGO Nomenclature (Montreal, 1994)
Table 9.2 Carcinoma of the Cervix Uteri: Stage Grouping
In a review of the literature, Hacker and Berek (12) reported that the overall accuracy for the detection of paraaortic lymph node metastases was 84.4%, with a false positive rate of approximately 21% (9 of 41 positive readings) and a false negative rate of approximately 13% (13 of 99 negative readings).
Magnetic Resonance Imaging Because CT cannot discriminate between cancer and normal soft tissue of the cervix and uterus, it is limited in the evaluation of early cervical cancer. Magnetic resonance imaging (MRI), which has been used since the early 1980s, has high-contrast resolution and multiplanar imaging capability and is a valuable modality for determining tumor size, degree of stromal penetration, vaginal extension, corpus extension, parametrial extension, and lymph node status (13) (Figure 9.4).
Subak et al. (14) evaluated CT or MRI before surgical exploration in 79 patients with FIGO stage IB, IIA, or IIB cervical carcinoma. They reported that MRI estimated tumor size to within 0.5 cm of the surgical specimen in 64 of 69 patients (93%) and had an accuracy of 78% for measuring depth of stromal invasion. By contrast, CT was unable to evaluate tumor size or depth of invasion. For the evaluation of stage of disease, MRI had an accuracy of 90% compared with 65% for CT (p <0.005), and it was also more accurate in assessing parametrial invasion (94% vs. 76%, p <0.005). Both modalities were comparable for the evaluation of lymph node metastases (each 86% accurate).
Narayan and colleagues from Melbourne reported that the cervical diameter determined by EUA correlated poorly with the MRI diameter, but the MRI diameter correlated strongly with the pathologic diameter after surgical removal of the specimen (p <0.0001) (15). The ability of MRI to more accurately determine tumor diameter and parametrial infiltration, particularly in patients with bulky cervical tumors, makes it a useful adjunct to clinical evaluation in treatment planning (16). MRI is also appropriate for the evaluation of pregnant patients because it poses no risk to the fetus (17).
A metaanalysis comparing the utility of lymphangiogram, CT, and MRI for the detection of pelvic and paraaortic lymph node metastases in patients with cervical cancer concluded that the three imaging modalities performed comparably (18).
Figure 9.4 MRI Scan showing a moderate sized cervical tumor with extension to the uterine corpus. (Scan courtesy of Dr Kailash Narayan, Melbourne, Australia.)
Positron Emission Tomography The positron emission tomgraphy (PET) imaging technique has been available in some centers since the mid-1990s. It depends on metabolic, rather than anatomic, alteration for the detection of disease. PET uses radionuclides, which decay with the emission of positrons (positively charged particles). Because cancer cells are avid users of glucose, a radionuclide-labeled analogue of glucose, 2-[18F] fluoro-2-deoxy-D-glucose (FDG), can be used to detect sites of malignancy by identifying sites of increased glycolysis. The PET scan has the potential to delineate more accurately the extent of disease, particularly in lymph nodes that are not enlarged and in distant sites that are undetectable by conventional imaging studies.
Rose et al. (19) performed PET scanning on 32 patients with stages IIB to IVA cervical cancer before surgical staging lymphadenectomy. For the paraaortic lymph nodes, PET scanning had a sensitivity of 75%, a specificity of 92%, a positive predictive value of 75%, and negative predictive value of 92%. In a study aimed at determining whether PET scanning could obviate the need for surgical staging, Narayan et al. reported a sensitivity of 83%, specificity of 92%, positive predictive value of 91%, and negative predictive value of 85% for 24 patients evaluable for pelvic nodal status (20). However, PET detected only four of seven (57%) cases of positive paraaortic nodes. All histologically confirmed nodes not visualized on PET were <1 cm in diameter.
Grigsby et al. retrospectively compared the results of CT lymph node staging with whole-body FDG-PET in 101 consecutive patients with cervical cancer who were referred for primary radiation therapy (21). CT demonstrated abnormally enlarged pelvic lymph nodes in 20 patients (20%) and paraaortic lymph nodes in seven (7%). PET demonstrated abnormal FDG uptake in pelvic nodes in 67 patients (67%), in paraaortic nodes in 21 patients (21%), and in supraclavicular nodes in eight patients (8%). For the 94 patients with negative paraaortic nodes on CT scan, the 2-year progression-free survival (PFS) was 64% in PET-negative patients and 18% in PET-positive patients (p <0.0001) (Fig. 9.5). A multivariate analysis demonstrated that the most significant factor for PFS was the presence of positive paraaortic lymph nodes as detected by PET imaging (p = 0.025).
Figure 9.5 Survival curves for patients with a negative CT scan in relation to PET scan status of the paraaortic lymph nodes. (Reproduced with permission from Grigsby PW, Siegel BA, Dehdashti F. Lymph node staging by positron emission tomography in patients with carcinoma of the cervix. J Clin Oncol 2001;19:3745-3749.)
The combined use of MRI and PET for pretreatment staging of nonoperable cervical cancer has led to a better understanding of the relationship between FIGO stage tumor volume and nodal metastases (22).
Extension of cervical cancer into the uterus can be readily detected by MRI. In univariate analysis, Narayan et al. reported a significant association between nodal involvement and both FIGO stage (p = 0.018) and uterine body involvement; in multivariate analysis, however, only uterine body extension was independently related to the risk of lymph node involvement (21). PET-documented pelvic node positivity was 75% (39 of 52) in patients with uterine extension as compared with 11% (2 of 18) in those without (p <0.001).
A recent analysis of 15 published PET studies in cervical cancer reported that the pooled sensitivity of FDG-PET for paraaortic lymph node metastases in cervical cancer was 84% [95% confidence interval (CI), 68%-94%], and the specificity 95% (95% CI, 89%-98%) (23).
Fine-Needle Aspiration Cytology If pelvic or abdominal masses or enlarged lymph nodes are detected during physical examination or imaging studies, fine-needle aspiration may be performed under CT or ultrasonic guidance. The procedure is performed under local anesthesia and is free of major complications, even in the presence of clotting problems or perforation of a hollow viscus. The reported accuracy for abdominopelvic nodes ranges from 74% to 95% (24,25). Only a positive cytologic diagnosis should be used as a basis for therapeutic decision making.
The inability of available noninvasive diagnostic tests to detect small lymph node metastases led many investigators in the 1970s to undertake pretreatment staging laparotomies to identify patients with positive paraaortic nodes. These patients were then treated with extended-field radiation to encompass the involved nodes.
The initial approach used was transperitoneal, but this was associated with a significant risk of postoperative adherent, fixed loops of bowel, and increased postradiation morbidity (26). Of the first 33 patients staged with this approach at the University of California, Los Angeles (UCLA), ten (30.3%) subsequently had small bowel complications requiring surgical correction (27). The complications included enterovaginal fistulas in five patients, small bowel obstruction in nine, and radiation enteritis in six.
After this experience, the UCLA group introduced the extraperitoneal approach (27). Although originally described through a left lateral J-shaped incision, it is most readily performed through a midline incision, which facilitates easy access to both sides of the pelvis. When closed with running PDS or Maxon Smead-Jones sutures, the midline incision does not delay the onset of radiation therapy. Before the node dissection, the peritoneum is opened, and a thorough exploration of the peritoneal cavity is carried out. The peritoneum is then stripped off the anterior and lateral abdominal wall to expose the pelvic sidewall on each side. Each round ligament must be transected extraperitoneally to facilitate exposure. The dissection may be extended cephalad as far as necessary by extending the lower midline incision around the umbilicus to the epigastrium.
Surgical complications of staging laparotomies include damage to the great vessels, particularly the inferior vena cava, and ureteric injury, but are infrequent in the hands of an experienced surgeon. In the GOG report of almost 300 patients (10), the operative mortality was 0.3% (one case), intraoperative injuries to the vein or ureter occurred in four cases (1.6%), and a postoperative urinary fistula or bowel obstruction occurred in seven patients (2.9%).
In the 1990s, some investigators proposed laparoscopic staging (28). This is discussed in Chapter 21.
In spite of the theoretical advantages of surgical staging, the benefits in terms of patient outcomes remain unproven. Lai et al., from Taipei, conducted a randomized trial to compare clinical with surgical staging for patients with locally advanced cervical cancer (29). Patients in the surgical arm were randomly allocated to either a laparoscopic or an extraperitoneal approach. Although paraaortic nodal metastases were documented in 25% of patients in the surgical arm, patient accrual was terminated after 61 patients were entered because interim analysis showed a significantly worse outcome in terms of progression-free survival (p = 0.003) and overall survival (p = 0.024) for patients in the surgical arm.
A retrospective review of three phase III Gynecologic Oncology Group studies (GOG 85, 120, and 165) was undertaken to compare the outcome for patients who had negative paraaortic lymph nodes by pretreatment surgical staging with that of patients who had only radiographic (CT or MRI) exclusion of paraaortic nodal disease before pelvic chemoradiation (30). There were 555 in the surgical staging group, and 130 in the radiographic group. In multivariate analysis, radiographic staging was associated with a poorer prognosis both for disease progression [hazard ratio (HR) 1.35; 95% CI, 1.01-1.81] and for death (HR 1.46; 95% CI, 1.08-1.99).
The results from the ongoing collaborative study of PET, MRI, and surgical staging being conducted by the American College of Radiology Imaging network and the GOG will help clarify whether or not there is any ongoing role for surgical staging in the PET scan era (available at http://www.clinicaltrials.gov). By constructing a mathematical model from the available literature, Petereit et al. predicted that surgical staging would save 2.6, 6, and 7 lives per 100 patients treated, for stages IB, IIB, and IIIB, respectively (31).
Patterns of Spread
Cervical cancer spreads by the following means:
Invasive cervical cancer, whether squamous or glandular, arises from intraepithelial neoplasia. Malignant cells penetrate the basement membrane, then progressively infiltrate the underlying stroma. They may progressively infiltrate laterally to involve the cardinal and uterosacral ligaments, superiorly to involve the uterine corpus, inferiorly to involve the vagina, anteriorly to involve the bladder, and posteriorly to involve the peritoneum of the pouch of Douglas and the rectum.
Cervical cancer can spread to all pelvic node groups, although the obturator nodes are most frequently involved. The parametrial nodes are not necessarily involved before the nodes on the pelvic sidewall. Although tumor cells can reach the common iliac and paraaortic nodes directly by the posterior cervical trunk (32), this is very uncommon, and lymph node spread in cervical cancer almost invariably occurs in an orderly fashion from the nodes on the pelvic sidewall to the common iliac and then the paraaortic group. From the paraaortic nodes, spread can occasionally occur through the thoracic duct to the left scalene nodes (29). The incidence of pelvic lymph node metastases in stage IB cervical cancer is shown in Table 9.3. The incidence of paraaortic nodal metastases in stages II and III cervical cancer is shown in Table 9.4.
Table 9.3 Incidence of Pelvic Lymph Node Metastases in Stage IB Cervical Cancer
The concept of sentinel node identification for cervical cancer was first introduced by Dargent in 2000 (52). Using a combination of patent blue dye and radiolabeled colloid injected into the cervix preoperatively, several authors have subsequently confirmed the ability to identify sentinel nodes in 70% to 100% of patients (53,54,55,56) (see Chapter 21). Sentinel nodes have usually been located in the hypogastric, external iliac, or obturator nodal groups but have also been reported in the common iliac and paraaortic region. In one patient, a sentinel node was found in the left groin (57).
Lymphatic invasion by tumor cells is commonly seen in the primary tumor, and tumor cells are also seen occasionally in lymphatic channels in the parametrium. Burghardt and Girardi (58) believe that tumor emboli are sometimes held up in a lymphatic vessel and grow to become foci of discontinuous parametrial involvement.
Table 9.4 Incidence of Paraaortic Lymph Node Metastases in Stages II and III Cervical Cancer
Ovarian involvement by cervical cancer is rare but most likely occurs through the lymphatic connection between the uterus and the adnexal structures (59). In a study of patients with clinical stage IB cervical cancer, the GOG reported ovarian spread in four of 770 patients (0.5%) with squamous carcinoma and in two of 121 patients (1.7%) with adenocarcinoma. All six patients with ovarian metastases had other evidence of extracervical spread (60).
Although spread to virtually all parts of the body has been reported, the most common organs for hematogenous spread are the lungs, liver, and bone.
Treatment of invasive cancer involves appropriate management for both the primary lesion and potential sites of metastatic disease. Both surgery and radiation therapy may be used for primary treatment, although definitive surgery is usually limited to patients with stages I or early IIA disease. Some European and Asian centers also treat patients with stage IIB disease with primary surgery (61,62,63).
The term microcarcinoma of the uterine cervix was first introduced by Mestwerdt (64) in the German literature in 1947. He suggested that 5 mm was the deepest penetration acceptable. Since then, both terminology and treatment have been the subject of much debate.
In 1961, the Cancer Committee of FIGO recommended that clinical stage I cervical cancer should be subdivided into stage IA and stage IB, and stage IA was vaguely defined as a preclinical cancer with early stromal invasion. This did little to clarify even the definition.
In 1974, the Committee on Nomenclature of the Society of Gynecologic Oncologists (SGO) in the United States proposed that microinvasive carcinoma should be defined as a lesion that invaded below the basement membrane to a depth of 3 mm or less, and in which there was no evidence of lymph-vascular space invasion. Although this definition provided no horizontal dimension, patients whose disease fulfilled these criteria were shown to have virtually no risk of lymph node metastases and to be adequately treated by either hysterectomy or cone biopsy (65,66,67).
In 1985, FIGO included measurements in the definition of stage IA disease for the first time (68). The new definition stated that stage IA was a preclinical carcinoma (i.e., diagnosed only by microscopy) and should be divided into two groups: stage IA1, in which there was minimal stromal invasion, and stage IA2, in which the depth of stromal invasion should not exceed 5 mm and the horizontal spread should not exceed 7 mm. Vascular space invasion did not influence the staging. This definition still failed to define the border between stage IA1 and IA2 lesions.
A more precise definition of microinvasive carcinoma was adopted by FIGO in 1995. Stage IA1 was defined as a tumor that invaded to a depth of 3 mm or less, whereas stage IA2 referred to a tumor that invaded to a depth greater than 3 mm and up to 5 mm. In both stages, the horizontal spread should not exceed 7 mm. Lymph-vascular space invasion was not included as part of the definition.
Stage IA1: Squamous Carcinoma
Although stromal invasion can be seen in small punch biopsies, a definitive diagnosis of microinvasion can be made only in conization (or hysterectomy) specimens (69). The conization specimen must be thoroughly sampled, not only to make the correct diagnosis but also to be certain about the margins.
In an extensive review of the literature, Ostor (70) reported that of 2,274 squamous lesions with invasion of less than 1 mm only three were cases of lymph node metastases (0.1%) and invasive recurrence developed in eight cases (0.4%). Among 1,324 squamous lesions invading between 1 and 3 mm, there were seven cases with lymph node metastases (0.5%) and 26 cases in which invasive recurrence developed (2%). No horizontal limitation was placed on these lesions, so they do not strictly fit the current FIGO definition of stage IA1 disease, and most of the cases were treated without lymph node dissection.
Studies of stage IA disease in patients meeting the 1995 FIGO definition are limited. Elliott and colleagues from Sydney reported 476 such patients (71). There were 418 (88%) squamous and 58 (12%) glandular tumors. Of 180 patients undergoing lymphadenectomy, the incidence of positive nodes in patients with stage IA1 disease was 0.8% (1 of 121 cases). Lee et al. (72) from South Korea reported positive nodes in three of 116 patients (2.6%) undergoing lymphadenectomy for stage 1A1 squamous cell carcinoma of the cervix.
Roman et al. (73) reported 87 cases of microinvasive carcinoma diagnosed on cone biopsy and followed by either repeat cone biopsy or hysterectomy. Significant predictors of residual invasion included status of the internal margin (residual invasion present in 22% of women with dysplasia at the margin vs. 3% with a negative margin; p <0.03) and the combined status of the internal margin and the postconization ECC (residual invasion 4% if both negative, 13% if one positive, and 33% if both positive; p <0.015). Depth of invasion and the number of invasive foci were not significant. The researchers concluded that if either the internal margin or the postconization ECC contained dysplasia or carcinoma, then the risk of residual invasion was high and warranted repeat conization before definitive treatment planning.
A study from Chang Mai, Thailand, confirmed these findings (74). Histopathology studies were reviewed from 129 patients who underwent hysterectomy following a cone biopsy that showed microinvasive squamous cell carcinoma. All had high-grade CIN or invasive carcinoma at the cone margins. Of the 129 patients, 77 (59.7%) had residual disease in the hysterectomy specimen, of whom 20 patients (15.5%) had residual invasive cancer: 18 were microinvasive and two were frankly invasive. Factors that significantly affected the risk of residual disease included positive postconization endocervical curettage (p = 0.001), positive cone margins for invasive cancer (p = 0.003), and depth of stromal invasion >1mm (p= 0.014). They also recommended repeat conization to determine the exact severity of the lesion before planning definite treatment.
Figure 9.6 Algorithm for the management of patients with a high-grade Pap smear and inadequate colposcopy or with microinvasive cervical carcinoma on punch biopsy.
In view of these considerations, a cone biopsy with clear surgical margins and a negative ECC should be considered adequate treatment for a patient with stage IA1 squamous carcinoma of the cervix. If future childbearing is not required, then extrafascial hysterectomy may be considered. If the cone margins or postconization ECC reveal high-grade dysplasia or microinvasive carcinoma, then a repeat conization should be performed before proceeding to simple hysterectomy because more extensively invasive disease may be present.
Lymph-vascular space invasion is uncommon in stage IA1 lesions, with Ostor (70) reporting an incidence of 15% from a literature review. Elliott et al. (71) reported lymph-vascular space invasion in 8.5% of tumors invading 1 mm or less, 19% between 1.1 and 2 mm, 29% between 2.1 and 3 mm, and 53% between 3.1 and 5 mm. Lee et al. (72) also found a positive correlation between depth of invasion and the presence of lymph-vascular space invasion but found no definite correlation between lymph-vascular space invasion (LVSI) and lymph node metastases, only two of their four patients with positive nodes having LVSI (72). Its significance in microinvasive cervical cancer remains controversial, and it is not mentioned in the FIGO definition. It probably should be disregarded when planning treatment, unless it is extensive. A proposed algorithm for the management of microinvasive cervical cancer is shown in Fig. 9.6.
Stage IA2: Squamous Carcinoma
In spite of the extensive literature on microinvasive cervical carcinoma, there is limited information available on lesions 3 to 5 mm deep with as much as 7 mm of horizontal spread (i.e., 1995 FIGO stage IA2 lesions). The 1985 FIGO definition of stage IA2 included all cases other than those with early stromal invasion, which usually meant approximately 1 mm of invasion. Hence, some large European studies of this group of patients would have underestimated the risk of lymph node metastases and invasive recurrence for patients whose tumors invaded 3 to 5 mm. For example, Kolstad (75), in a review of 411 patients with 1985 FIGO stage IA2 squamous carcinoma of the cervix, reported only four cancer-related deaths (1%) and 12 local recurrences (2.9%). Similarly, Burghardt et al. (76) reported two pelvic sidewall recurrences after abdominal hysterectomy among 89 patients (2.2%). A local recurrence developed in three other patients (3.4%). Four of the five recurrences had vascular space invasion.
Investigators in the United States have tended to separate lesions with invasion of 3 mm or less and no vascular space involvement from stage IA2 lesions because such cases met the SGO criteria for conservative management. Therefore, a few publications, mainly from the United States, have reported cases with stromal invasion of 3 to 5 mm, although most have not included the horizontal dimension currently required in the FIGO definition. The overall incidence of lymph node metastases in such cases was 7.1%, although it varied from 0% to 13.8% (Table 9.5). The incidence of invasive recurrence was 3.6%, and 2.9% of patients died of their disease. Most patients were treated by radical hysterectomy and pelvic lymph node dissection.
Table 9.5 Incidence of Lymph Node Metastases with Stromal Invasion of 3 to 5 mm—Horizontal Dimension Not Stated
Takeshima et al. (82) reported that, of 73 patients with depth of invasion between 3 and 5 mm, the incidence of lymph node metastasis was 3.4% for tumors with a horizontal spread of 7 mm or less and 9.1% for those with greater than 7 mm spread. Elliott et al. also reported positive nodes in 3.4% of patients (2 of 59) with stage IA2 cervical cancer (71).
It is apparent that more data are needed for this group of patients, and it is hoped that the Cancer Committee of FIGO will not change the current definition of microinvasion so that more information can be obtained about the risk of lymph node metastases and the risk of recurrence with various treatment approaches.
Our recommended treatment for stage IA2 squamous carcinoma of the cervix is modified radical hysterectomy and pelvic lymph node dissection. In a medically unfit patient, intracavitary radiation may be used.
Many patients with early cervical cancer are young, and preservation of fertility is a major concern. Consequently, surgical approaches that remove the primary lesion and regional lymph nodes, while conserving the corpus for future childbearing, have been explored.
Cone biopsy and extraperitoneal lymphadenectomy have been used in the past, but in 1994 Dargent et al. pioneered the use of radical trachelectomy and laparoscopic pelvic lymphadenectomy (83). A nonabsorbable cervical cerclage is usually placed around the uterine isthmus at the time of the trachelectomy. Several other groups have subsequently confirmed that the operation is feasible in experienced hands, that cure rates are high, and that subsequent pregnancies can be carried to viability in many cases (See Table 21.3). Covens et al. (84) reported an actuarial conception rate at 12 months of 37% following radical trachelectomy on 30 patients with stage IA-early IB disease (85).
Radical abdominal trachelectomy was first reported by Smith et al. in 1997 (85). One advantage of this approach is that the anatomy is more familiar to most gynecologic oncologists. Although the procedure has not yet gained wide acceptance, successful pregnancy outcomes have been reported (86).
Although radical trachelectomy is associated with less operative time and short-term morbidity than radical hysterectomy, there are some long-term morbidities. In a retrospective review of 29 patients undergoing radical trachelectomy, the group from St. Bartholomew's Hospital in London reported dysmenorrhea in 24%, irregular menstruation in 17%, recurrent candidiasis in 14%, cervical suture problems in 14%, isthmic stenosis in 10%, and prolonged amenorrhea in 7% of patients (87).
A critical issue for trachelectomy by either route is the extent of tumor extension up the endocervical canal. An adequate endocervical surgical margin is mandatory if local recurrence is to be avoided, so some type of preoperative imaging is desirable. Magnetic resonance imaging appears to be highly sensitive and specific for the determination of tumor extension beyond the internal os (88).
Although the concept of microinvasive squamous carcinoma is well accepted, the concept for the glandular counterpart is more controversial, partly because of the lack of available data, but also because of the difficulty in accurately determining the true extent of glandular lesions. Microinvasion has usually been reported as depth of invasion or tumor thickness of 5 mm or less, the measurement being taken from the mucosal surface (89,90) or from the base of the surface epithelium (91). Width and volume of tumor involvement have varied considerably, and only recently have reports looked specifically at microinvasion as now defined by the FIGO staging.
Most cases arise adjacent to the transformation zone, although Teshima et al. (92) reported that three of 30 cases (10%) arose outside the transformation zone. Adenocarcinoma in situ may extend up the entire endocervical canal, and invasion may occur at any point (92). Lee and Flynn (93), in a study of 40 cases of adenocarcinoma invasive to 5 mm or less, reported that in 78% of the cases, the midpoint of the invasive focus was in the region of the transformation zone. The endometrioid variant was particularly likely to arise higher in the canal.
Whereas squamous lesions are usually unifocal, glandular lesions are sometimes multifocal. Ostor et al. (90) reported that 21 of 77 cases (27.3%) were multicentric, meaning that both cervical lips were affected, without continuity around the “edges” at 3 and 9 o'clock. They reported no “skip” lesions, which they arbitrarily defined as separation between discrete microinvasive adenocarcinomas in the same lip of greater than 3 mm. More than one focus of invasive disease was present in four of 40 cases (10%) reported by Lee and Flynn (93).
Positive lymph nodes have rarely been reported in FIGO stage IA1 lesions, although Elliott reported a solitary nodal metastasis in a patient with <1 mm stromal invasion (71). Berek and co-workers (89), in a report of 102 patients with primary adenocarcinoma of the cervix from UCLA, reported no lymph node metastases in patients whose tumor was less than 2 cm in diameter, although two of 18 patients (11.1%) with 2 to 5 mm of invasion had positive nodes. Kaku et al. (91) reported recurrences at the vaginal vault in two of 30 patients (6.7%) with less than 5 mm of invasion. One patient had a tumor volume of 1,222 mm3, but the other had a tumor with a depth of 3.9 mm and a width of 4.9 mm (i.e., FIGO stage IA2). The only adenocarcinoma recurrence in the 77 patients reported by Ostor et al. (90) involved a patient whose tumor invaded to a depth of 3.2 mm but was 21 mm in length (i.e., stage IB1).
A study from Melbourne reported 29 patients with stage IA1 and 9 with stage IA2 microinvasive adenocarcinoma of the cervix (94). A variety of treatment methods were used. Cone biopsy of the cervix was performed in 18 patients, including two with stage IA2 disease. No recurrences were noted during an average follow-up of 72 months. In a literature review, the same authors noted positive nodes in 12 of 814 patients (1.5%) undergoing pelvic lymph node dissection for microinvasive adenocarcinoma of the cervix. Lymph-vascular space invasion was present in 25 patients (3%), all without lymph node involvement (94).
The Surveillance, Epidemiology, and End Results (SEER) database was used to identify 131 cases of stage IA1 and 170 cases of stage IA2 adenocarcinoma of the cervix treated between 1988 and 1997 (95). There was no histologic review, and patients were treated in a variety of ways from cone biopsy to radical hysterectomy and pelvic lymphadenectomy. Simple hysterectomy alone was used for 118 patients (39.2%). With a mean follow-up of 46.5 months, the censored survival was 99.2% for patients with stage IA1 disease and 98.2% for stage IA2.
In view of these observations, it seems reasonable to treat the disease in a similar manner to its squamous counterpart. A cone biopsy with negative margins appears to be adequate treatment for the primary lesion if fertility is desired (96), particularly in the absence of lymph-vascular space invasion. The cone biopsy should be a cold knife procedure; loop excision procedures obscure depth of invasion, and margins and are not acceptable either for diagnosis or therapy (97). Following childbearing, it seems reasonable to recommend hysterectomy because Pap smears and colposcopy are less reliable, and Poynor et al. (98) reported that ECC was positive before cervical conization in only 43% of patients with glandular lesions.
Stage IB1 and Early Stage IIA Cervical Cancer
In 1994, FIGO recognized the prognostic significance of tumor size by subdividing stage IB disease into stage IB1 (primary lesion ≤4 cm diameter) and stage IB2 (primary lesion >4 cm diameter).
Patients with stage IB1 are universally regarded as being ideal candidates for radical hysterectomy and pelvic lymphadenectomy, although equal cure rates may be obtained with primary radiation therapy (99). The choice of modality should depend mainly on the availability of the appropriate expertise. Since the introduction of fellowship training in gynecologic oncology, expertise in radical pelvic surgery has become widely available in the United States and most developed countries. The Patterns of Care study in the United States suggests that the same may not be true for radiation oncology, particularly outside of tertiary referral units (100). If both surgical and radiotherapeutic expertise are available, then radiation is usually reserved for the surgically unfit patient. Chronologic age should not be considered a contraindication to radical surgery because elderly patients experience morbidity similar to that of younger patients (101).
Primary surgery has the advantage of removing the primary disease and allowing accurate surgical staging, thereby allowing any adjuvant therapy to be more accurately targeted. In addition, it avoids the possible chronic radiation damage to the bladder, small and large bowel, and vagina, which is difficult to manage. Surgical injuries to the same organs are more readily repaired because the blood supply is not compromised. Sexual dysfunction is, in general, underreported but is a problem for many patients who have had both external-beam therapy and brachytherapy because of vaginal atrophy, fibrosis, and stenosis (102). Although the vagina is shortened by approximately 1.5 cm after radical hysterectomy, it is more elastic; in premenopausal patients, ovarian function can be preserved. In postmenopausal patients, the nonirradiated vagina responds much better to estrogen therapy.
Influence of Diagnostic Conization
The influence of previous cone biopsy on the morbidity of radical hysterectomy is controversial. Samlal et al. (103) reported no significant difference in morbidity, but the conization-radical hysterectomy interval in their study was 6 weeks. They believed that delaying the definitive surgery may allow the tissue reaction to subside, thereby decreasing morbidity. Others have found that the interval between the conization and radical hysterectomy has no influence on morbidity, and they recommend proceeding without delay (104). Our policy is to proceed immediately with radical hysterectomy if the surgical margins of the cone biopsy are involved but to postpone surgery for 6 weeks if the cone margins are clear.
Types of Radical Hysterectomy
In 1974, Piver et al. (105) described the following five types of hysterectomy: extrafascial, modified radical, radical, extended radical, and partial exenteration.
Extrafascial Hysterectomy (Type I) This is a simple hysterectomy and is suitable for stage IA1 cervical carcinoma.
Modified Radical Hysterectomy (Type II) This is basically the hysterectomy described by Ernst Wertheim (106). The uterine artery is ligated where it crosses the ureter, and the medial half of the cardinal ligaments and proximal uterosacral ligaments are resected. Piver et al. (105) described removal of the upper one-third of the vagina, but this is rarely necessary unless vaginal intraepithelial neoplasia (VAIN) 3 is extensive. The operation described by Wertheim involved selective removal of enlarged nodes rather than systematic pelvic lymphadenectomy. The modified radical hysterectomy is appropriate for stage IA2 cervical cancer.
Radical Hysterectomy (Type III) The most commonly performed operation for stage IB cervical cancer is that originally described by Meigs in 1944 (107). The uterine artery is ligated at its origin from the superior vesicle or internal iliac artery, allowing removal of the entire width of the cardinal ligaments. Piver (105) originally described excision of the uterosacral ligaments at their sacral attachments and resection of the upper half of the vagina. Such extensive dissection of the uterosacral ligaments and vagina is seldom required for stage IB cervical cancer.
Extended Radical Hysterectomy (Type IV) This differs from the type III operation in three aspects: (i) The ureter is completely dissected from the vesicouterine ligament, (ii) the superior vesicle artery is sacrificed, and (iii) three-fourths of the vagina is excised. The risk of ureteric fistula is increased with this procedure, which Piver (105) used for selected small central recurrences after radiation therapy.
Partial Exenteration (Type V) The indication for this procedure was removal of a central recurrence involving a portion of the distal ureter or bladder. The relevant organ was partially excised and the ureter reimplanted into the bladder. This procedure is occasionally performed if cancer is found to be unexpectedly encasing the distal ureter at the time of radical hysterectomy. Alternatively, the operation may be aborted and the patient treated with primary radiation.
A new classification for radical hysterectomy was described following a consensus meeting in Kyoto, Japan, which was arranged by Shingo Fujii in February 2007 (108). The classification is based only on the lateral extent of the resection. Four basic types are described, A-D, adding when necessary a few subtypes that consider nerve preservation and paracervical lymphadenectomy. Lymph node dissection is considered separately, and four levels (1,2,3,4) are defined according to the corresponding arterial anatomy and the radicality of the procedure. A description of the procedures from the original paper by Querleu and Morrow is given below.
Type A: Minimum Resection of Paracervix
This is an extrafascial hysterectomy. The paracervix is transected medial to the ureter but lateral to the cervix. The uterosacral and vesicouterine ligaments are not transected at a distance from the uterus. Vaginal resection is generally at a minimum, routinely less than 10 mm, without removal of the vaginal part of the paracervix (paracolpos).
Type B: Transection of the Paracervix at the Ureter
This type has two levels:
B1—Without removal of lateral paracervical lymph nodes
B2—With removal of lateral paracervical nodes
Partial resection of the uterosacral and vesicouterine ligaments is a standard part of this category. The ureter is unroofed and rolled laterally, permitting transection of the paracervix at the level of the ureteral tunnel. The neural component of the paracervix caudal to the deep uterine vein is not resected. At least 10mm of the vagina from the cervix or tumor is resected.
The operation corresponds to the modified or proximal radical hysterectomy and is adapted to early cervical cancer. The radicality of this operation can be improved without increasing postoperative morbidity by lymph node dissection of the lateral part of the paracervix, thus defining two subtypes—B1 and B2—with additional removal of the lateral paracervical lymph nodes.
The border between paracervical and iliac or parietal lymph node dissection is defined arbitrarily as the obturator nerve: Paracervical nodes are medial and caudal. The combinatiuon of paracervical and parietal dissections is simply a comprehensive pelvic node dissection. The lateral part of the paracervix has traditionally been resected fully in so-called types III to IV or distal radical hysterectomy.
The morbidity of type B2 does not differ from that of B1, although the combination of B1 with paracervical lymph node dissection may be equivalent to that of type C1 resection.
In type C, the paracervix is transected at the junction with the internal iliac vascular system and has two types:
C1—With nerve preservation
C2—Without preservation of autonomic nerves
This type involves transection of the uterosacral ligament at the rectum and vesicouterine ligament at the bladder. The ureter is mobilized completely, and 15-20 mm of vagina from the tumor or cervix and the corresponding paracolpos is resented routinely, depending on vaginal and paracervical extent and on surgeon choice.
Type C corresponds to variants of classical radical hysterectomy. By contrast with types A and B, in which the autonomic nerve supply to the bladder is not threatened, the issue of nerve preservation is crucial. Two subcategories are defined: C1 with nerve preservation and C2 without preservation of autonomic nerves. In C1, the uterosacral ligament is transected after separation of the hypogastric nerves. The bladder branches of the pelvic plexus are preserved in the lateral ligament of the bladder (i.e., lateral part of bladder pillar). If the caudal part of the paracervix is transected, then careful identification of bladder nerves is needed.
For C2, the paracervix is transected completely, including the part caudal to the deep uterine vein.
In type D, the entire paracervix is resected:
D1—Resection of the entire paracervix along with the hypogastric vessels
D2—Resection of the entire paracervix, along with the hypogastric vessels and adjacent fascial or muscular structure
This group of rare operations feature additional ultraradical procedures, mostly indicated at the time of pelvic exenteration. Type D1 is resection of the entire paracervix at the pelvic sidewall along with the hypogastric vessels, exposing the roots of the sciatic nerve. There is total resection of the vessels of the lateral part of the paracervix. These vessels (i.e., inferior gluteal, internal pudendal, and obturator vessels) arise from the internal iliac system.
Type D2 is D1 plus resection of the entire paracervix with the hypogastric vessels and adjacent fascial or muscular structures. This resection corresponds to the LEER (laterally extended endopelvic resection) procedure (109).
Lymph Node Dissection
Lymph node dissection has four levels:
Level 1—External and internal iliac
Level 2—Common iliac (including presacral)
Level 3—Aortic inframesenteric
Level 4—Aortic infrarenal
This classification ignores the widely used pelvic versus paraaortic dissection, in which the limit of the pelvis dissection is around the midcommon iliac area.
Within every level, and independently from each other, several types of lymph node dissection must be defined to describe adequately the radicality of the procedure: diagnostic (minimum sampling of sentinel node only, removal of enlarged nodes only, or random sampling); systematic lymph node dissection; and debulking (resection of all nodes >2cm) (110).
Technique for Radical Hysterectomy
The patient is given prophylactic antibiotics for 24 hours, and pneumatic calf compressors are used during and after surgery until the patient is fully mobilized. In addition, prophylactic subcutaneous heparin is given for 5 days after surgery.
Incision The abdomen may be opened either through a lower midline incision extending to the left of the umbilicus or through a low transverse Maylard or Cherney incision. The low transverse incision, which is described in Chapter 20, requires division of the rectus abdominis muscle but provides excellent exposure of the primary tumor and pelvic sidewalls. The midline incision, which can be readily extended, provides better exposure of the paraaortic region, but this is seldom necessary for early stage cervical cancer.
Exploration After entering the peritoneal cavity, all organs are systematically palpated, and any evidence of metastatic spread is documented by frozen section. The vesicouterine fold and pouch of Douglas peritoneum are examined for evidence of tumor infiltration, and the tubes and ovaries are examined for any abnormalities. Any bulky pelvic or paraaortic nodes are removed and frozen sections obtained to differentiate between inflammatory and malignant changes.
Radical Hysterectomy With the uterus under traction, the retroperitoneum is entered through the round ligaments bilaterally. The ureter is identified as it crosses the pelvic rim, and the pelvic sidewall spaces are developed by a combination of sharp and blunt dissection (Figs. 9.6, 9.7).
The paravesicle space (Fig. 9.7) is bordered by:
The pararectal space is bordered by:
The floor of the spaces is formed by the levator ani muscle.
Bladder Takedown The vesicouterine fold of peritoneum is opened and the bladder dissected off the anterior cervix and upper vagina. This should be done before any blood supply is ligated, because occasionally tumor may infiltrate into the bladder base, making hysterectomy impossible. Rather than resecting the relevant section of the bladder in this situation, the abdomen is usually closed and the patient treated with primary radiation.
Ligation of the Uterine Artery The uterine artery usually arises from the superior vesicle artery, close to its origin from the hypogastric artery. The artery is ligated at its origin in a type III or type C radical hysterectomy, or at the point where it crosses the ureter in the modified or type B radical hysterectomy, then mobilized over the ureter by gentle traction and dissection. The uterine veins must be identified and clipped or troublesome bleeding will occur.
Figure 9.7 Paravesicle and pararectal spaces.
Dissection of the Ureter The roof of the ureteric tunnel is the anterior vesicouterine ligament. This can be taken down in a piecemeal fashion bilaterally (Fig. 9.8), thereby avoiding the troublesome venous bleeding that can occur by blindly advancing a right-angled forceps into the tunnel. Each ureter is mobilized off its peritoneal attachment fairly low in the pelvis to avoid unnecessary stripping from its peritoneal blood supply. It is also mobilized off the side of the uterus. This exposes the posterior or caudal vesicouterine ligament, which is also divided in a type III hysterectomy but not in a type II procedure. The anterolateral surface of the distal ureter is left attached to the bladder in a further effort to preserve the blood supply. If the caudal vesicouterine ligament is transected, then it is desirable to identify and preserve the bladder branch from the inferior hypogastric plexus (111,112).
Posterior Dissection The peritoneum across the pouch of Douglas is incised and the rectovaginal space identified by posterior traction on the rectum. The rectum is taken off the posterior vagina and the uterosacral ligaments using sharp and blunt dissection, and the latter are divided at the rectum (type III or C) or closer to the cervix (type II or B) (Fig. 9.9).
Lateral Dissection After division of the uterosacral ligaments, the cardinal ligaments (paracervix) are clamped at the level of the pelvic sidewall (type III or C) or more medially (type II or B), after which two more clamps are usually required across the paravaginal tissues to reach the vagina. If the ovaries are to be removed, then the infundibulopelvic ligaments are divided at this stage. If they are to be retained, then they are freed from the fundus by transecting the ovarian ligament and fallopian tube.
Vaginal Resection The length of vagina to be removed depends on the nature of the primary lesion and the colposcopic findings in the vagina. If the primary lesion is confined to the cervix and there is no evidence of VAIN, it is necessary to resect only 1.5 to 2 cm of upper vagina. This is achieved by entering the vagina anteriorly and transecting it with a knife or scissors. The vault is closed, making sure to avoid “dog ears.” The vaginal angles are sutured to the paravaginal tissues and uterosacral ligaments.
Figure 9.8 Piecemeal dissection of anterior vesicouterine ligament.
Figure 9.9 The pelvic ligaments and spaces.
Figure 9.10 The pelvic and paraaortic lymph nodes and their relationship to the major retroperitoneal vessels.
Pelvic Lymphadenectomy Once the uterus has been removed, the pelvic sidewall exposure is excellent. If there are any bulky positive pelvic or paraaortic lymph nodes confirmed by frozen section, our policy is to remove only the enlarged nodes and rely on external-beam radiation to sterilize any micrometastases. If there are no suspicious nodes, then full pelvic lymphadenectomy is performed (Fig. 9.10). Using sharp dissection with Metzenbaum scissors, all fatty tissue is stripped off the vessels from the midcommon iliac region to the circumflex iliac vein distally, preserving the genitofemoral nerve on the psoas muscle. The obturator fossa is entered by retracting the external iliac artery and vein medially, then stripping the fatty tissue off the pelvic sidewall. All fatty tissue is then sharply dissected out of the obturator fossa, taking care particularly to avoid the obturator nerve, which enters the fossa at the bifurcation of the common iliac vein. An accessory obturator vein is seen in at least 30% of patients and is easily torn if not identified. It enters the distal external iliac vein inferiorly.
Postextirpation The peritoneal cavity is irrigated with warm water or saline. The pelvic peritoneum is not closed, and no drains are used unless there is concern about hemostasis. When the retroperitoneal space is left open and prophylactic antibiotics are used, drains may actually increase febrile morbidity, pelvic cellulitis, and length of postoperative ileus (113). A suprapubic catheter is placed in the bladder and the abdomen closed with a continuous mass closure technique.
Table 9.6 Postoperative Complications of Radical Hysterectomy
Complications of Radical Hysterectomy
The average blood loss reported is usually between 500 (114) and 1,500 dL (115). Intraoperative injuries occasionally occur to the pelvic blood vessels, ureter, bladder, rectum, or obturator nerve. These injuries should be recognized immediately and repaired. Even complete severance of the obturator nerve does not usually cause significant problems with walking.
Detailed information about postoperative morbidity is infrequently supplied. Table 9.6 gives data from three series from which detailed information is available. It can be seen that urinary tract infection is the most common complication, related to the need for prolonged catheter drainage. Other febrile morbidity from such causes as atelectasis or wound infection is also relatively common. Prolonged ileus occasionally occurs and, in our experience, may result from lymphatic ascites that can develop following lymphadenectomy(117). It may require repeated paracenteses but will eventually settle completely. Venous thrombosis is undoubtedly underdiagnosed, but with proper prophylactic measures, pulmonary embolism is infrequent. Vesicovaginal or ureterovaginal fistulas occur in approximately 1% of cases.
Bladder Dysfunction The most distressing late complication is prolonged bladder dysfunction, necessitating voiding by the clock with the aid of the abdominal muscles, and, in some cases, self-catheterization. Covens and colleagues (118) reported a significant difference in the incidence of bladder dysfunction at 3 months among different surgeons at the University of Toronto. Twenty-one percent of patients reported objective or subjective bladder dysfunction, but the range among the eight surgeons concerned varied from 0% to 44%. Samlal et al. (115) from Amsterdam, using a more radical dissection of the cardinal ligaments than is usually done in the United States (Okabayashi technique), reported a 5.2% incidence of this complication.
Voiding difficulties and bowel dysfunction are inevitable in the immediate postoperative period, and suprapubic or urethral catheter drainage and laxatives are desirable for at least the first 5 days. If cystometry is performed to evaluate bladder dysfunction, two abnormal patterns are found (119). The hypertonic bladder with elevated urethral pressure is most common. The hypotonic bladder occurs much less frequently. Patients with a hypertonic pattern have the normal bladder-filling sensation and the usual discomfort of a full bladder. The condition is selflimiting, usually within 3 weeks of surgery. The prognosis is much worse for patients with a hypotonic bladder, and some of these patients eventually require lifelong self-catheterization.
Sexual Dysfunction A large Swedish study of sexuality in cervical cancer survivors reported sexual dysfunction in 55% of patients treated by radical hysterectomy alone (120). Problems included insufficient lubrication, reduced genital swelling at arousal, reduced vaginal length and elasticity, and dyspareunia. The addition of preoperative brachytherapy or external beam radiation yielded no excess risk of sexual dysfunction.
This is in marked contrast to our own experience at the Royal Hospital for Women, where Grumann et al., in a more detailed study of a much smaller group of patients, reported that radical hysterectomy was not associated with major sexual sequelae (121).
The differences between the two groups may be explained by the radicality of the surgery. We do not take more than 1.5 cm of normal vagina at radical hysterectomy, so reports of vaginal shortness are very unusual.
Other studies have also reported a favorable outcome in terms of sexual function following radical hysterectomy (122,123), and the nerve sparing operation is likely to further enhance sexual function, particularly in terms of orgasmic sensation and vaginal lubrication.
To avoid bowel, bladder, and sexual dysfunction, a nerve-sparing radical hysterectomy has been developed (111, 112,124,125,126). The operation seems to be associated with prompt recovery of bladder function and minimal need for self-catheterization (127,128). From the superior hypogastric plexus located over the sacral promontory, two hypogastric nerves containing sympathetic fibers run into the small pelvis beneath the ureter and are responsible for such functions as bladder compliance, urinary continence, and small muscle contractions at orgasm. The hypogastric nerves fuse with parasympathetic fibers of the pelvic splanchnic nerves, coming from sacral roots 2.3 and 4, to form the inferior hypogastric plexus, which is situated in the dorsal part of the parametrium and the dorsal vesicouterine ligament. The parasympathetic fibers are responsible for vaginal lubrication and genital swelling during sexual arousal, detrusor contractility, and various rectal functions.
Performance of the nerve-sparing operation, as described by Trimbos and colleagues (112), involves three basic steps: (i) The hypogastric nerve is identified and preserved as it runs in a loose sheath beneath the ureter and lateral to the uterosacral ligament, (ii) the inferior hypogastric plexus is lateralized and avoided during parametrial dissection, and (iii) the most distal part of the inferior hypogastric plexus is preserved during the dissection of the posterior or caudal part of the vesicouterine ligament.
Nerve sparing occurs inevitably with a more conservative type of radical hysterectomy. A prospective, randomized study of type II versus type III radical hysterectomy for stages IB to IIA cervical cancer was reported by Landoni et al. (131). There was no significant difference in recurrence rate (24% type II vs. 26% type III) or the number of patients dead of disease (18% type II vs. 20% type III) for the two procedures, but urologic morbidity was significantly reduced with the less radical operation (13% vs. 28%).
Tumors less than 2 cm in diameter, with <10mm of stromal invasion, no vascular space invasion and negative lymph nodes have <10% risk of parametrial invasion (132,133). Further study is warranted to determine the feasibility of omitting parametrectomy in these low-risk patients (133).
Lymphedema As a late complication of pelvic lymphadenectomy, lymphedema is underreported in the medical literature. In a study of 233 patients having pelvic lymphadenectomy in our center, 47 (20.2%) developed lymphedema (134). The onset of the swelling was within 3 months in 53%, within 6 months in 71%, and within 12 months in 84% of patients. The addition of pelvic radiation postoperatively increased the risk of lymphedema.
Stage IB2 Cervical Carcinoma
Optimal management of patients with primary tumors greater than 4 cm in diameter is controversial. Local, regional, and distant failure are more likely than for stage IB1 lesions whatever primary modality of treatment is chosen. Most patients are cured, so quality of life is an important issue, and properly randomized trials are necessary to determine the best approach.
Primary Radiation Therapy
There is a strong correlation between tumor size and outcome for patients with stage IB cervical cancer (135). Perez and colleagues from St. Louis reported 10-year disease-free survival rates of 90% for stage IB tumors <2 cm, 76% for 2-4 cm, 61% for 4.1-5 cm, and 47% for >5 cm (136). For lesions <2 cm doses of 75 Gray (Gy) to point A resulted in pelvic failure rates of 10%, whereas for more extensive lesions, even doses of 85 Gy resulted in 35-50% pelvic failure rates (136). A recent study from Cambridge reported a local control rate of only 66.7% for 12 patients with stage IB2 cervical cancer, yet three patients (25%) had grade 3 or 4 late toxicity (137).
Bulky tumors require aggressive radiotherapy, and complication rates are high. Perez et al. (138), in a study of 552 patients with stages IB to IIA cervical cancer treated with radiation alone, reported grade 3 morbidity in 7% of cases with grade 2 morbidity in a further 10% of cases. Grade 3 morbidity included six rectovaginal fistulae, one rectouterine fistula, five vesicovaginal fistulae, one enterocolic fistula, one enterocutaneous fistula, one sigmoid perforation, seven rectal strictures, ten ureteral strictures, and ten small bowel obstructions. Montana et al. (139) reported grade II and III morbidity in 8% of cases of stage IB squamous carcinoma treated with radiation alone and noted a relationship between the dose to point A and the dose to the bladder and rectum, as well as the incidence of complications.
Currently, chemoradiation is usually given in line with reports for advanced cervical cancer (140).
Radiation and Extrafascial Hysterectomy
In 1969, Durrance et al. (141) initially reported that central failure could be reduced from 15% (14 of 94 patients) to 2.6% (1 of 39 patients) by the addition of extrafascial hysterectomy following primary pelvic radiation. The GOG recently reported the results of a trial of 256 eligible patients with tumors ≥4 cm diameter who were randomized between radiation alone (n = 124) and attenuated radiation followed by extrafascial hysterectomy (n = 132) (142). Twenty-five percent of patients had tumors ≥7 cm diameter. There was a lower incidence of local relapse in the hysterectomy group (27% vs. 14% at 5 years), although outcomes were not statistically different. Their conclusions were somewhat ambiguous: “Overall, there was no clinically important benefit with the use of extrafascial hysterectomy. However, there is good evidence to suggest that patients with 4, 5, and 6 cm tumors may have benefited from extrafascial hysterectomy.”
Chemoradiation and Extrafascial Hysterectomy
A 1999 GOG study (143) of bulky (≥4 cm) cervical cancers randomly assigned patients to be treated with radiation therapy (external beam and intracavitary cesium) and adjuvant extrafascial hysterectomy 3 to 6 weeks later, with or without weekly cisplatin during the external radiation. Cisplatin was to be delivered at a dose of 40 mg/m2 (maximum dose, 70 mg/week) weekly for 6 weeks. There were 374 patients entered into the study. Residual cancer in the hysterectomy specimen was significantly reduced in the group receivingcisplatin (47% vs. 57%). Survival at 24 months was significantly improved by the addition of cisplatin (89% vs. 79%), as was recurrence-free survival (81% vs. 69%). Grades 3 and 4 hematologic and gastrointestinal toxicities were more frequent in the group receiving cisplatin, whereas other toxicities were equivalent in both treatment arms.
In 1993, Sardi et al. (144) reported the results of a randomized trial of neoadjuvant chemotherapy for patients with bulky stage IB cervical cancer. In the control arm (75 patients), a Wertheim-Meigs operation followed by adjuvant whole-pelvic radiation was carried out, whereas in the neoadjuvant group (76 patients), the same procedures were preceded by three cycles of chemotherapy with the “quick” vincristine, bleomycin, and cisplatin (VBP) regimen. The chemotherapy protocol consisted of cisplatin 50 mg/m2 on day 1, vincristine1 mg/m2 on day 1, and bleomycin 25 mg/m2 on days 1, 2, and 3 (the latter given as a 6-hour infusion). Three cycles were given at 10-day intervals. Survival and progression-free interval were significantly improved for patients with an echographic volume greater than 60 dL, mainly because of a decrease in the incidence of locoregional failures. In the control group, pelvic recurrences were observed in 24.3% of patients compared with 7.6% of patients in the neoadjuvant group.
A 2002 metaanalysis was reported using updated individual patient data from five randomized controlled trials conducted worldwide between 1988 and 1999 that compared neoadjuvant chemotherapy plus surgery with radiotherapy alone (145). There were 872 patients in the metaanalysis and 368 deaths. The overall results showed a highly significant benefit for the neoadjuvant chemotherapy and surgery arm with a 36% reduction in the risk of death and an absolute improvement in survival of 15% at 5 years. An updated metaanalysis using data from 28 trials and more than 3,000 patients revealed that favorable outcomes were only obtained if the chemotherapy cycle length was 14 days or shorter or the cisplatin dose intensity was at least 25 mg/m2 per week (146).
Figure 9.11 Radical hysterectomy specimen from a patient with an exophytic stage IB2 cervical cancer.
Primary Radical Hysterectomy and Tailored Postoperative Radiation
Our preferred option for the management of stage IB2 carcinoma of the cervix is primary radical hysterectomy and postoperative adjuvant radiation, with or without chemotherapy, depending on the operative findings (Fig. 9.11). This philosophy is also applied to patients with stage IIA disease, provided the tumor does not come down the anterior vaginal wall. Our approach to stage IB or IIA cervical cancer is shown in Fig. 9.12. Older patients tolerate radical surgery remarkably well, although approximately 10% of patients older than 70 years of age have a medical contraindication to surgery (101). Radiation tolerance in elderly patients is controversial. Although comparable outcomes to younger patients have been reported (147), others have indicated that comorbid conditions in the elderly necessitate more frequent treatment breaks and less ability to deliver intracavitary therapy, thereby impairing overall prognosis (148).
There are several advantages to a primary surgical approach. First, it allows for accurate staging of the disease, thereby allowing adjuvant therapy to be modified according to needs (149). Second, it allows resection of bulky positive lymph nodes, thereby improving the prognosis significantly (110,150). Third, it allows removal of the primary cancer, thereby avoiding the difficulty of determining whether there is viable residual disease after the cervix has responded to radiation. Finally, for most premenopausal patients, it allows preservation of ovarian function. A primary surgical approach is mandatory in patients with acute or chronic pelvic inflammatory disease, anatomic problems making optimal radiation therapy difficult, or an undiagnosed coexistent pelvic mass (151).
In a retrospective study comparing radical hysterectomy for stage IB1 versus IB2 disease, Finan et al. (39) reported no significant increase in morbidity for patients with stage IB2 disease. They noted positive nodes in 15.5% of patients (28 of 181) with stage IB1 disease versus 43.8% (21 of 48) with stage IB2. Positive paraaortic nodes were present in 1.8% of patients having paraaortic dissection for stage IB1 disease (2 of 111) versus 6.3% of patients with stage IB2 (2 of 32). These patients cannot be salvaged without extended-field radiation (47).
In addition, approximately half of the patients with positive nodes have bulky nodal metastases. These patients are also unlikely to be salvaged without resection of the bulky nodes, but if the bulky nodes are resected and the patient is given adjuvant radiation, then the prognosis is converted to that of a patient with nodal micrometastases (110,150).
Figure 9.12 Algorithm for the management of stages IB and early IIA carcinoma of the cervix. RT, radiation therapy; GOG, Gynecologic Oncology Group.
In the report by Finan et al. (39), positive surgical margins were noted in 5.0% of patients (9 of 181) with stage IB1 disease versus 12.5% of patients (6 of 48) with stage IB2. In addition, 77% of patients (27 of 35) with stage IB2 disease had more than 15 mm of stromal invasion compared with 27.3% of patients (30 of 110) with stage IB1.
Although the optimal management of patients with stage IB2 disease awaits further randomized, prospective studies, our own experience and that of others (151,152,153,154,155,156,157) suggests that good survival rates with tolerably low morbidity can be achieved with a primary surgical approach, giving tailored postoperative radiation in the majority of cases.
In the only randomized, prospective study looking at radical surgery versus primary radiation for stage IB to IIA cervical cancer, Landoni et al. (99) reported that for patients with a cervical diameter larger than 4 cm, the rate of pelvic relapse in the group treated with radiation therapy was more than twice the rate of distant relapse (30% vs. 13%). In addition, there was a significantly higher rate of pelvic relapse among those who had radiation alone (16 of 54; 30%) compared with those who had surgery plus adjuvant radiation (9 of 46; 20%).
To determine the cost-effectiveness of the three common strategies for managing stage IB2 squamous carcinoma of the cervix, Rocconi et al. created a decision-analysis model(158). They chose a hypothetical cohort of 10,000 patients, which they estimated to be the number of new cases of stage IB2 cervical cancer diagnosed in the United States every 5 years. They assumed all patients were diagnosed and clinically staged by a gynecologic oncologist and that each patient underwent a CT scan of the pelvis and abdomen to exclude advanced disease. A literature review was undertaken to determine grades 3 and 4 complication and disease-free survival rates for each modality, and costs were calculated for each 10,000 patient cohort.
Radical hysterectomy with pelvic and paraaortic lymphadenectomy and tailored chemoradiation for high-risk patients was the least expensive strategy, with a cost of $284 million per 10,000 women and a 5-year disease-free survival of 69% (158). Neoadjuvant chemotherapy followed by radical hysterectomy and tailored chemoradiation for high-risk patients had an estimated cost of $299 million (DFS 69.3%), whereas primary chemoradiation had an estimated cost of $508 million and a disease-free survival of 70%. They concluded that primary surgery was the most cost-effective strategy and that neoadjuvant chemotherapy would cost approximately $500,000 per additional survivor, and primary chemoradiation an additional $2.2 million per additional survivor.
Table 9.7 Survival after Radical Hysterectomy for Stages IB and IIA Cervical Cancer
Prognostic Factors for Stages IB to IIA
The major prognostic factors for patients having radical hysterectomy and pelvic lymphadenectomy for stages IB to IIA cervical cancer are as follows:
Lymph Node Status
The most important prognostic factor is the status of the lymph nodes. Survival data for patients with positive nodes are shown in Table 9.7. The influence of the number of positive nodes is shown in Table 9.8. Patients with a single positive node below the common iliac bifurcation have a prognosis similar to that of patients with negative nodes (166,169,170). Patients with positive paraaortic nodes treated with extended-field radiation have a 5-year survival rate of approximately 50% (110,171).
Tumor Size, Depth of Stromal Invasion, Lymph-Vascular Space Invasion
In 1989, the GOG (170) published the results of a prospective clinicopathologic study of 732 patients with stage IB cervical carcinoma treated by radical hysterectomy and bilateral pelvic lymphadenectomy. Of these, 645 patients had no gross disease beyond the cervix or uterus and negative paraaortic nodes. One hundred patients had micrometastases in pelvic nodes, but their survival was not significantly different from patients with negative nodes.
Table 9.8 Five-Year Survival Rate (%) versus Number of Positive Pelvic Nodes in Stage IB Cervical Carcinoma
Figure 9.13 Disease-free survival for patients with cervical cancer after radical hysterectomy and bilateral pelvic lymphadenectomy. (From Delgado G, Bundy B, Zaino R, Sevin B-U, Creasman WT, Major F. Prospective surgical-pathological study of disease-free interval in patients with stage IB squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study. Gynecol Oncol 1990;38:352-357, with permission.)
There were three independent prognostic factors:
A relative risk (RR) was calculated for each prognostic variable and an overall estimate of risk determined by multiplying the appropriate RR for the three independent variables. For example, a tumor 4 cm in diameter was estimated to have a RR of 2.9. If it invaded 12 mm into the outer third of the cervix, then the RR was estimated to be 37. Lymph-vascular space invasion conferred a RR of 1.7. The overall estimate of risk was therefore 2.9 × 37 × 1.7 = 182.4. The latter figure may be termed the GOG score. Disease-free survival curves were constructed for several RR groups (Fig. 9.13). It can be seen that the likelihood of recurrence for a patient with a GOG score greater than 120 is 40% at 3 years.
The extent of lymph-vascular space invasion varies markedly between tumors, and Roman et al. (172) have shown that the quantity of lymph-vascular space invasion correlates significantly with the risk of nodal metastases in women with early stage cervical cancer. The quantity of LVSI, as defined by the percentage of all histologic sections with LVSI and the total number of foci with LVSI, has also been shown to be an independent prognostic factor for time to recurrence in women with early stage squamous carcinoma of the cervix (173).
Burghardt et al. (174) analyzed 1,004 cases of stage IB, IIA, or IIB cervical carcinoma treated by radical hysterectomy at Graz, Munich, and Erlangen, with all surgical specimens processed as giant sections. This processing technique allows accurate assessment of tumor volume and parametrial extension. The 5-year survival rate for 734 patients with no parametrial extension was 85.8% compared with 62.4% for 270 patients with parametrial extension.
The group at Yale (175) reported that patients with parametrial extension, regardless of lymph node status, had a significantly shorter disease-free interval than patients with positive nodes alone, with 12 of 19 such patients (63%) recurring in the pelvis. By contrast, a Japanese study of 117 patients with stages IB to IIB disease and parametrial invasion after radical hysterectomy were divided into two groups based on the status of the pelvic lymph nodes. Five-year overall survival for node-positive and node-negative patients was 52% and 89%, respectively (p = 0.0005) (176). Extrapelvic recurrence was more common in patients with positive nodes (p = 0.005).
Histologic Cell Type
Small-cell carcinoma of the cervix is uncommon but has an unequivocally poor prognosis (177).
The prognostic significance of adenocarcinoma histologic type is more controversial. These tumors usually arise in the endocervical canal and diagnosis is often delayed, so it is difficult to be certain that lesions of comparable size are being compared. Many centers report adenocarcinoma histologic type as a poor prognostic factor in multivariate analysis(166,178,179), but Shingleton et al. (180) were unable to confirm this. In a patient care evaluation study of the American College of Surgeons, they evaluated 11,157 patients from 703 hospitals with cervical cancer treated in 1984 and 1990. There were 9,351 cases of squamous carcinoma (83.8%), 1,405 cases of adenocarcinoma (12.6%), and 401 cases of adenosquamous carcinoma (3.6%). In a multivariate analysis of patients with clinical stage IB disease, histologic type had no significant effect on survival.
The prognostic significance of adenosquamous carcinoma of the cervix is also controversial, with some authors reporting a significantly worse prognosis for patients with these tumors (181,182), whereas others report no difference from squamous lesions with respect to metastatic potential or outcome (183,184). Farley et al. investigated 185 women with pure adenocarcinomas (AC) and 88 women with adenosquamous carcinomas (ASC) (185). They reported no difference in survival for patients with FIGO stage I disease (AC, 89%; ASC 86%; p = 0.64) but a significantly decreased median and overall survival for adenosquamous carcinoma in patients with advanced disease (FIGO stages II to IV).
Close Vaginal Margins
Investigators at the Jackson Memorial Hospital in Miami, Florida, reviewed the charts of 1,223 patients with stages IA2, IB, or IIA cervical cancer who had undergone radical hysterectomy (165). Fifty-one patients (4.2%) had positive or close vaginal margins, the latter being defined as tumor no more than 0.5 cm from the vaginal margin of resection. Twenty-three of these cases had negative nodes and no parametrial involvement, and 16 of the 23 (69.6%) received postoperative radiation. The 5-year survival rate was significantly improved by the addition of adjuvant radiation (81.3% vs. 28.6%; p <0.05). They recommended that close vaginal margins without other high-risk factors should be considered a poor prognostic variable.
Several newer markers have been reported to have prognostic value in early stage cervical cancer.
Serum Squamous Cell Carcinoma Antigen Level The group at Groningen, the Netherlands, have demonstrated that increased pretreatment serum squamous cell carcinoma antigen (SCC-Ag) levels correlate strongly with FIGO stage, tumor size, deep stromal invasion, and lymph node metastases (186). Even in node-negative patients, the risk of recurrence was three times higher if the SCC-Ag level was elevated before surgery. A Japanese study recommended routine SCC-Ag monitoring following treatment because the overall survival was higher when recurrence was predicted on the basis of tumor marker elevation than when diagnosed by other modalities (p = 0.03) (187). The prediction of isolated paraaortic lymph node recurrence significantly correlated with SCC-Ag elevation as an initial sign (p = 0.001).
Human Papilloma Virus Genotype Cervical tumors associated with HPV type 18 have been associated with an increased risk of recurrence and death in patients with surgically treated cervical cancer (188,189). It has also been suggested that HPV-18-containing tumors may progress to invasion without a prolonged preinvasive phase (190).
Microvessel Density Because angiogenesis is considered essential for tumor growth and the development of metastases, it is not surprising that high microvessel density has been reported adversely to influence survival in clinical stage IB cervical cancer and to identify patients with negative nodes at risk for relapse (191).
Adjuvant pelvic radiation following radical hysterectomy should be given in two circumstances: (i) patients with positive nodes, positive parametria, or positive surgical margins; and (ii) patients with negative nodes but high-risk features in the primary tumor.
Patients with Positive Nodes, Positive Parametria, or Positive Surgical Margins
In 2000, the Southwest Oncology Group (SWOG) and Gynecologic Oncology Group reported results of a randomized study of women with FIGO stages IA2, IB, and IIA carcinoma of the cervix found to have positive pelvic lymph nodes, positive parametrial involvement, or positive surgical margins at the time of primary radical hysterectomy and pelvic lymphadenectomy (192). Patients had to have confirmed negative paraaortic nodes. The regimens were as follows:
Regimen I—external pelvic radiation with cisplatin and 5-fluorouracil (5-FU) infusion
Regimen II—external pelvic radiation
Patients on regimen I received intravenous cisplatin 70 mg/m2 followed by a 96-hour continuous intravenous infusion of 5-FU (4,000 mg/m2) every 3 weeks for four courses. Radiation therapy in both arms delivered 4,930 centiGray (cGy) to the pelvis using a four-field box technique. Patients with metastatic disease in high common iliac nodes also received 4,500 cGy to a paraaortic field.
The 3-year survival rate for women on the adjuvant chemotherapy plus radiation arm was 87%, compared with 77% for women receiving adjuvant radiation alone. This difference was statistically significant.
A follow-up report was published in 2005 (193). The absolute improvement in 5-year survival for adjuvant chemotherapy in patients with tumors ≤2 cm was only 5% (77% versus 82%), whereas for tumors >2 cm it was 19% (58% versus 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%).
Patients with Negative Nodes but High-Risk Features in the Primary Tumor
Although patients with negative nodes have an 85% to 90% survival rate after radical hysterectomy and pelvic lymphadenectomy, they contribute approximately 50% of the treatment failures, with most of the failures (about 70%) occurring in the pelvis (194).
In 1999, the GOG reported the results of a randomized study of adjuvant whole-pelvic radiation at a dose of 50.4 Gy versus no further treatment after radical hysterectomy for patients with high-risk, node-negative stage IB cervical cancer (195). To be eligible for the study, patients had to have at least two of the following risk factors: greater than one-third stromal invasion, lymph-vascular space invasion, and large tumor size (usually ≥4 cm). There were 277 patients entered into the study. The addition of radiation significantly reduced the risk of recurrence with a recurrence-free rate of 88% for radiation versus 79% for observation at 2 years. Severe (GOG grades 3 to 4) gastrointestinal or urologic toxicity occurred in 6.2% of patients receiving radiation versus 1.4% of controls.
An update of this GOG study was reported in 2006, which included seven additional recurrences and 19 additional deaths (196). The radiation therapy arm continued to show a statistically significant reduction in risk of recurrence, but the improvement in overall survival with radiation did not reach statistical significance (HR = 0.70, 90% CI 0.45-1.05; p = 0.074). Postoperative radiation appeared to be particularly beneficial for patients with adeno or adenosquamous histologies.
The group from Leiden University in the Netherlands identified 51 patients (13%) who had two of the three high-risk factors identified by the GOG, among 402 patients who underwent radical hysterectomy for early stage cervical cancer (197). They compared 34 patients (66%) who received postoperative pelvic radiation with 17 patients (33%) who did not. A statistically significant difference was found in 5-year cancer-specific survival in favor of the high-risk group treated with pelvic radiation (86% versus 57%).
Radiation morbidity is highly correlated with the target volume, and a clinical review of our experience in patients with stage IB, node-negative, cervical cancer at the Royal Hospital for Women in Sydney revealed that 87% of recurrences occurred in the central pelvis (vaginal vault or paravaginal soft tissues). We therefore decided to pilot a study involving a radiation field focused on the central pelvis to see if the central failure rate could be decreased without causing significant morbidity. The results were reported in 1999 (198). The portals for the standard and small-pelvic radiation fields used on patients treated at the Royal Hospital for Women are shown in Table 9.9 (Fig. 9.14). The small field decreases the amount of small and large bowel that is irradiated.
Table 9.9 Anteroposterior and Lateral Portals for Standard and Small-Field Pelvic Radiation Used for Patients from the Royal Hospital for Women, Sydney
Figure 9.14 Comparison between (A) standard field and (B) small field for pelvic radiation.
High-risk, node-negative patients were selected on the basis of a GOG score of at least 120 (Fig. 9.13). Twenty-five consecutive patients were selected with a mean GOG score of 166 (range 120 to 263). With a mean follow-up of 32 months (range 12 to 64 months), there was only one recurrence (4%) at 16 months. A log-rank analysis demonstrated a significant improvement in the 5-year disease-free survival rate when this group was compared with the high-risk patients in the GOG study (GOG score >120) who were observed without postoperative radiation (p = 0.005) (198). No major morbidity occurred, but minor morbidity was recorded in four patients: lymphedema in three and mild rectal incontinence in one.
A 2003 Japanese study compared adjuvant small-field pelvic radiation for 42 patients with high-risk, node-negative stage I or II cervical cancer with whole-pelvic radiation for 42 patients with node-positive disease (199). The 5-year pelvic control rate was 93% in the small-pelvic field cohort and 90% in the whole-pelvic field group. They concluded that small-pelvic field radiation appeared to be adequate for high-risk node-negative patients. The same group subsequently reported decreased haematologic and gastrointestinal toxicity with the small field technique (200).
Adjuvant Chemotherapy after Radical Hysterectomy
Japanese workers have reported a favorable outcome for intermediate and high-risk patients treated with adjuvant chemotherapy following radical hysterectomy (201). Intermediate risk was defined as stromal invasion >50% (n = 30), whereas high risk was defined as positive surgical margins, parametrial invasion, or lymph node metastases, (n = 35). Three courses of bleomycin, vincristine, mitomycin C, and cisplatin were given for intermediate risk cases, and 5 courses for high-risk cases. Estimated 5-year disease-free survival was 93.3% for the 30 patients with intermediate-risk tumors, and 85.7% for the 35 with high-risk tumors. The incidence of locoregional recurrence was 3.3% in the intermediate-risk group and 8.6% in the high-risk group.
Stages IIB to IVA Disease
Primary Radiation Therapy
Radiation therapy can be used to treat all stages of cervical cancer, but for early stage disease it is usually reserved for medically unfit patients. Radical external-beam radiation therapy plus brachytherapy is the gold standard for advanced disease, but as the volume of the primary lesion increases, the likelihood of sterilizing it with radiation decreases. Increasing the dose of radiation increases the late morbidity to the bowel, bladder, and vaginal vault, so various strategies have been investigated to try to improve local control.
Strategies that have been investigated include:
Hyperfractionated radiation has not been adequately studied for cervical cancer (202), and trials of neoadjuvant chemotherapy followed by radiation have generally been disappointing. A metaanalysis from the United Kingdom looked at updated individual patient data from 18 randomized controlled trials conducted worldwide between 1982 and 1995 (203). There was a high level of statistical heterogeneity, although trials using a higher dose intensity of cisplatin and shorter cycle length appeared to increase survival, whereas a lower dose intensity and longer cycle length appeared to reduce survival.
Hydroxyurea and misonidazole are the best-studied radiation sensitizers (204), but they have been shown to be inferior to cisplatin-based chemoradiation (140).
Concurrent Chemotherapy and Radiation
Three large randomized prospective trials, all reported in 1999, have established chemoradiation as the treatment of choice for patients with advanced cervical cancer.
The GOG reported the results of a phase III randomized study of external-beam pelvic radiation and intracavitary radiation combined with concomitant hydroxyurea versus weeklycisplatin versus 5 FU-cisplatin and hydroxyurea (HFC) in 526 patients with stages IIB, III, and IVA cervical cancer who had undergone extraperitoneal surgical sampling of the paraaortic lymph nodes. Women with intraperitoneal disease or disease metastatic to the paraaortic lymph nodes were ineligible (140). Chemotherapy regimens were as follows:
Regimen I—weekly cisplatin 40 mg/m2/week for 6 weeks
Regimen II—hydroxyurea orally 2 mg/m2 twice weekly for 6 weeks, 5-FU 1,000 mg/m2/day as a 96-hour infusion on days 1 and 29, cisplatin 50 mg/m2 days 1 and 29
Regimen III—hydroxyurea orally 3 g twice weekly
Both platinum-containing regimens improved the PFS compared with hydroxyurea alone (p <0.005). The percentage of patients recurrence free at 24 months was 70% for weeklycisplatin, 67% for HFC, and 50% for hydroxyurea. Grade 3 or 4 leukopenia and grade 4 gastrointestinal toxicity were increased with HFC compared with weekly cisplatin orhydroxyurea (p = 0.0001 and p = 0.02, respectively). The investigators concluded that weekly cisplatin was more effective than hydroxyurea and more tolerable than HFC as a concomitant chemoradiation regimen for locally advanced cervical cancer.
Long-term follow-up of these patients confirmed improved progression-free and overall survival for both cisplatin containing arms compared with hydroxyurea (p <0.001) (205). The relative risk of progression of disease or death was 0.57 (95% CI, 0.43 to 0.75) with cisplatin and 0.51 (95% CI, 0.38 to 0.67 with cisplatin-based combination chemotherapy compared with hydroxyurea. The improved survival occurred collectively and individually for patients with stages IIB and III disease.
The Radiation Therapy Oncology Group (RTOG) randomized 403 patients with advanced cervical cancer confined to the pelvis between pelvic and paraaortic radiation, and pelvic radiation with concurrent cisplatin and 5-fluorouracil (206). With a median follow-up of 43 months, the actuarial survival at 5 years was 73% among patients having chemoradiation and 58% among those having radiation alone (p = 0.004). Disease-free 5-year survivals were 67% in the chemoradiation arm and 40% in the radiation alone arm, respectively (p<0.001). The rates of distal metastases and locoregional recurrences were significantly higher among patients treated with radiation alone.
The GOG-SWOG groups randomized 388 patients with FIGO stages IIB, III, or IVA disease and negative paraaortic nodes at retroperitoneal paraaortic lymph node sampling between standard pelvic radiation with hydroxyurea and standard pelvic radiation with 5-fluorouracil and cisplatin (207). Both progression-free (p = 0.03) and overall survival (p = 0.02) were significantly better for patients randomized to receive 5 FU-cisplatin.
Since publication of these clinical trials and the NCI clinical announcement in 1999, there has been a significant change in the management of cervical cancer in the United States, with the number of patients receiving concurrent chemoradiation increasing from 20% in 1997 to 72% in 2001 (208).
The optimal regimen for the chemotherapy is yet to be defined, but single-agent cisplatin at a dose of 40 mg/m2 given weekly during external beam therapy is widely used. The high rates of chemotherapy completion achieved in multiinstitutional trials can be difficult to reproduce in standard practice, and toxicity may be higher than reported, possibly because patients on trials are younger and have less comorbidity (209).
Stage IIIB Cervical Cancer with Hydronephrosis
There are two criteria for the diagnosis of stage IIIB cervical cancer: (i) tumor fixation to the pelvic sidewall or (ii) the presence of hydronephrosis. When the tumor is not fixed to the pelvic sidewall and the level of ureteric obstruction is above the main tumor mass, it is most likely the result of external ureteric compression from enlarged pelvic or paraaortic lymph nodes. Resection of these nodes via an extraperitoneal approach before radiation therapy can markedly improve survival (110,150).
If bulky nodal metastases are not resected, survival is significantly compromised. Data from the Mallindkrodt Institute of Radiology in St. Louis reveal that PFS at 5 years was 35% in patients with hydronephrosis and tumor fixed to the pelvic sidewall but decreased to 23% for 16 patients who presented with hydronephrosis without sidewall fixation (p <0.001) (210). When the level of ureteric obstruction was below the pelvic brim, 5-year PFS was 39%, but this fell to 22% when the obstruction was above the brim (p = 0.02).
Patients with bilateral hydronephrosis and a creatinine clearance <50 mL/min should be considered for elective ureteral stenting before the commencement of radiation therapy (211).
Clinical staging fails to detect extension of disease to the paraaortic lymph nodes in approximately 7% of patients with stage IB disease, 17% with stage IIB, and 29% with stage III (Table 9.4). Such patients will have a “geographic” treatment failure if standard radiation therapy ports are used.
As a routine procedure, operative staging has failed to realize its intended goal of substantially increasing survival. There are three principal reasons for this. First, patients with positive paraaortic nodes often have occult distant metastases and therefore require an effective systemic chemotherapy. Second, failure to control the pelvic disease has contributed significantly to the poor overall survival for this group of patients (Table 9.10). Finally, if it is assumed that approximately 25% of patients will have positive paraaortic nodes and approximately 25% of these will benefit from extended-field radiation (Table 9.11), it is evident that only 6% or so of patients undergoing a staging laparotomy will have a survival benefit as a consequence of the altered therapy. Greater survival benefits will accrue to patients with earlier stage disease because of the better pelvic disease control.
Table 9.10 Sites of Recurrence in Patients with Cervical Cancer Having Extended-Field Radiation for Positive Paraaortic Nodes
Because of the demonstrated high incidence of positive paraaortic lymph nodes in patients with advanced cervical cancer, prophylactic extended-field radiation may be justified in view of the acceptable incidence of complications in the absence of previous laparotomy (215).
The RTOG in the United States conducted a randomized trial of prophylactic paraaortic radiation (4,500 cGy) in 330 patients with stages IB and IIA (>4 cm) or IIB cervical cancer(216). Patients with lymphangiographic or surgical evidence of paraaortic nodal involvement were excluded. Significantly better 5-year survival rates (66% vs. 55%) were demonstrated for the patients receiving extended-field radiation therapy. In addition, patients treated with pelvic radiation alone had a higher risk of distant failure (32% vs. 25%). Severe gastrointestinal morbidity was more common in the group receiving extended-field therapy but was mainly seen in patients having previous abdominal surgery.
Table 9.11 Survival after Extended-Field Radiation
The GOG conducted a trial of extended-field chemoradiation for patients with biopsyproven paraaortic lymph node metastases (217). The radiation dose to the paraaortic area was 4,500 cGy, and the chemotherapeutic regime was 5-fluorouracil 1,000 mg/m2/day for 96 hours and cisplatin 50 mg/m2 in weeks 1 and 5. There were 86 evaluable patients with stages IB to IVA disease, and the 3-year overall and progression-free survivals were 39% and 34%, respectively. Severe acute toxicity was mainly gastrointestinal (18.6%) and hematologic (15%), and the major late morbidity was gastrointestinal (14% actuarial risk at 4 years). This trial demonstrated the feasibility of extended-field chemoradiation and confirmed that not all patients with paraaortic nodal metastases have systemic disease.
For patients without proven paraaortic nodal disease, the RTOG study reported in 1999 demonstrated that pelvic radiation plus concurrent chemotherapy was superior to prophylactic extended-field radiation without chemotherapy (206).
Our practice is to still give extended-field chemoadiation to the level of the superior border of L1 for patients with proven common iliac or paraaortic lymph node metastases, although the dose of cisplatin frequently has to be reduced. Extended-field intensity and modulated radiation with concurrent cisplatin has been reported to give good locoregional control, with distant metastases being the predominant mode of failure (218).
Plan of Management for Advanced Cervical Cancer
In view of the aforementioned results, our current approach to patients with advanced cervical cancer at the Royal Hospital for Women in Sydney is summarized in Fig. 9.15. All patients are subjected to a chest, pelvic, and abdominal CT scan and a PET scan. If there are systemic metastases, palliative pelvic radiation is given. Pretreatment laparotomy is undertaken if there is (i) adnexal pathology, (ii) pelvic or paraaortic lymph nodes at least 2 cm diameter, and (iii) no systemic metastases. Enlarged nodes are resected by an extraperitoneal approach because of the evidence strongly suggesting that such an approach converts the prognosis to that of patients with micrometastases (110,150). Patients with bulky positive nodes that have been resected from the pelvic or paraaortic area are given extended-field radiation with weekly cisplatin 30-40 mg/m2, and all other patients are given pelvic chemoradiation.
Figure 9.15 Algorithm for the management of patients with advanced cervical cancer. RT, radiation therapy.
Table 9.12 Carcinoma of the Cervix Uteri: Patients treated in 1999 to 2001: Survival by FIGO Stage (n = 11,639)
Stage IVA Disease with Vesicovaginal or Rectovaginal Fistula An occasional patient in Western countries has a vesicovaginal or rectovaginal fistula at presentation. If a CT scan of the chest, pelvis, and abdomen or a PET scan demonstrates no evidence of systemic disease, then these patients are suitable for primary pelvic exenteration.
The survival of patients with cervical cancer according to the Annual Report on the Results of Treatment in Gynaecological Cancer is shown in Table 9.12. Older patients have a lower survival for any given stage. Differences resulting from case mix, age group, type of tumor, and other factors may be responsible for variations or differences between centers.
After radiation therapy, the patient should be monitored monthly for the first 3 months. Regression may continue throughout the period, but if any progression of disease occurs, histologic confirmation should be obtained and consideration given to surgery.
After the immediate postradiation surveillance or postoperative checkup, patients are usually seen every 3 months until 2 years, every 6 months until 5 years, and annually thereafter. The role of routine follow-up has been questioned because most recurrences are detected at self-referral because of symptoms (219). Nevertheless, follow-up also allows psychosocial support for the patient as well as data collection; in a Dutch study, 32% of all cases of recurrence were diagnosed at routine follow-up (219). The mean disease-free interval was 18 months.
At each visit, patients should be questioned about symptoms, and physical examination should include assessment of the supraclavicular and inguinal nodes, as well as abdominal and rectovaginal examination. A Pap smear should be obtained at each visit. Chen et al. (220) reported that 72% of vaginal recurrences were asymptomatic, and most had an abnormal cytologic smear. The others were detected by noting ulceration on visual inspection or by palpation of a nodule or cuff induration.
Because the only realistic chance of cure is in patients with a central pelvic recurrence, it is not necessary routinely to obtain a chest radiograph or CT scan of the pelvis or abdomen. Any symptoms (e.g., cough) should be promptly investigated.
Whole-body FDG-PET appears to be a sensitive and specific tool for the detection of recurrent cervical cancer in patients who have clinical findings suspicious for recurrence (221). It has also been reported to be a sensitive modality for the detection of recurrent cervical cancer in asymptomatic patients. A study of 121 consecutive patients from the Republic of Korea reported a sensitivity of 96.1%, a specificity of 84.4%, and an accuracy of 91.7% for detection of recurrent disease (222). These authors suggested that the earlier diagnosis may have a favorable impact on survival. The PET scan has limitations in the detection of lesions less than 1 cm3 (223).
Nonsquamous Histologic Types
Adenocarcinomas currently represent 20% to 25% of cervical cancers in the industrialized countries. In the United States, the age-adjusted incidence rates for adenocarcinoma have increased by 29.1% since the mid-1970s, and the proportion of adenocarcinomas relative to squamous carcinomas has increased by 95.2% (224). Age-adjusted cervical adenocarcinoma incidence rates have also increased throughout Europe, particularly in younger women (225).
Most of this relative increase is related to a decreasing incidence of squamous carcinomas secondary to screening programs, but oral contraceptive use has been implicated in the absolute increase in adenocarcinomas in women younger than 35 years of age (226).
In England, the substantial increase in adenocarcinomas in recent years has been largely attributed to a birth-cohort effect, presumably associated with greater exposure to human papilloma virus after the sexual revolution of the 1960s (227). A Canadian study reported HPV in 70% of cases (53 of 77) with HPV 16 the predominant type (228). There was no correlation between HPV status and outcome. It is likely that HPV vaccination (229) and better cytologic and HPV screening (230) will reverse this trend in the future.
Adenocarcinomas are generally regarded as being more radioresistant than squamous carcinomas. In the Italian randomized study of radical surgery versus radiation therapy for stages IB to IIA cervical cancer, 46 of 343 patients (13.4%) had adenocarcinomas (99). Surgery and radiation therapy were found to be identical in terms of 5-year survival and disease-free survival rates for the entire group, but for patients with adenocarcinomas, surgery was significantly better in terms of both overall survival (79% vs. 59%, p = 0.05) and disease-free survival rates (66% vs. 47%, p = 0.02).
Workers in the Netherlands have shown that pretreatment serum CA125 levels are of prognostic significance for adenocarcinomas (231). The 5-year survival rate for stage IB adenocarcinomas was 52.4% when CA125 levels were elevated versus 95.6% when normal levels were present (p <0.01). Similarly, 42% of patients with elevated serum CA125 levels had lymph node metastases versus 4% when normal levels were found (p = 0.012). Although the prognostic significance of adenocarcinoma is somewhat controversial, the presence of lymph node metastases seems to portend a much worse prognosis for patients with adenocarcinomas than squamous carcinomas (115,224,232).
Adenosquamous carcinomas represent approximately 20% to 30% of all adenocarcinomas of the cervix. Most studies report a poorer outcome, although interpretation of the literature is confounded by a failure of investigators to adopt uniform criteria for diagnosis. The main issue is whether to include poorly differentiated squamous cell carcinomas in which the glandular elements are identified only by the use of mucin stains.
In the largest series of surgically staged IB cases, Helm et al. (233) matched 38 patients with adenosquamous carcinomas with patients with other histologic subtypes of adenocarcinoma with respect to stage, lesion size, nodal status, grade of adenocarcinoma, and age at diagnosis. Diagnosis was based on hematoxylin and eosin staining without use of mucin staining. Glassy cell carcinomas were included. Overall 5-year survival and disease-free survival rates for the matched adenosquamous and adenocarcinomas were not significantly different (83% vs. 90% and 78% vs. 81%, respectively), but the mean time to recurrence was significantly shorter in the adenosquamous group: 11 versus 32 months (p = 0.003). In addition, six patients with adenosquamous carcinomas could not be matched. Five of these had positive nodes in association with lesions measuring between 2 and 4 cm in diameter, and one had an 8-cm lesion with negative nodes.
Similar findings were reported from the M.D. Anderson Cancer Center comparing 29 patients with stage IB1 adenosquamous carcinoma with 97 patients with stage IB1 adenocarcinoma of the cervix undergoing radical hysterectomy. The authors reported no difference in recurrence rates between the two histologic groups, but the time to recurrence was shorter for patients with adenosquamous carcinoma (7.9 months vs. 15 months; p = 0.01) (184).
Glassy Cell Carcinoma
In 1956, Glucksman and Cherry (234) defined “glassy cell” carcinoma of the cervix as a poorly differentiated adenosquamous carcinoma, the cells of which had a moderate amount of cytoplasm and a typical “ground glass” appearance. Survival was poor, regardless of the mode of therapy. In 1982, Maier and Norris (235) suggested that poorly differentiated largecell, nonkeratinizing squamous carcinomas have a similar histologic appearance. Subsequently, Tamimi et al. (236) reviewed their experience with undifferentiated large-cell nonkeratinizing carcinomas of the cervix at the University Hospital in Seattle, Washington, and reported 29 cases over an 8-year period. The mean age of the patients was 31 years, and all cases were stage IB. All but one case was treated by radical hysterectomy, and the survival rate was 55%. In all but one case, the interval to recurrence was less than 8 months. The researchers concluded that the poor prognosis ascribed to the classically defined glassy cell carcinoma also holds true for this extended group of large-cell undifferentiated cervical cancers that display similar histologic features.
A contemporary series of 22 patients from the University of Washington suggests a better prognosis than previously reported (237). The overall survival for the series was 73%, with the overall survival for patients having stage I disease being 86% (12 of 14). Pelvic relapse was associated with lymph-vascular space invasion, deep stromal invasion, and large tumor size.
The term adenoma malignum of the cervix was first used in 1870 by Gusserow to describe a very highly differentiated adenocarcinoma. McKelvey and Goodlin (238) reported five cases in 1963, four of which were fatal within 4 years of presentation. They pointed out the deceptively benign histologic appearance of the tumor and stated that “if a lesion can be recognized as malignant by the usual criteria for adenocarcinoma of the cervix, it should be excluded from the adenoma malignum group.” McKelvey and Goodlin suggested that these tumors were radioresistant.
In 1975, Silverberg and Hurt (239) reported five additional cases. All patients were treated by modern radiotherapeutic techniques, and four of the five were long-term survivors. The authors believed that, with proper therapy, the tumor was no more malignant than might be expected for a highly differentiated adenocarcinoma, and they suggested the nameminimal deviation adenocarcinoma.
An association has been noted with Peutz-Jeghers syndrome, as well as with sex-cord tumors with annular tubules, a distinctive ovarian neoplasm with features intermediate between those of the granulosa and Sertoli cell type (240).
These tumors represent approximately 1% of adenocarcinomas of the cervix and occur mainly in the fifth and sixth decades (241). Diagnosis is often delayed because Pap smears may be normal or show very minor abnormalities.
Clinically, patients usually present with a watery or mucous discharge or with abnormal uterine bleeding. On physical examination, the cervix is usually firm and indurated (242).Punch biopsy is not helpful, and deep wedge or cone biopsy is necessary to demonstrate the depth of glandular penetration.
Radical hysterectomy, bilateral salpingo-oophorectomy, and pelvic lymphadenectomy is the treatment of choice for operable cases, and the prognosis for such cases appears to be very good (242). For more advanced cases, lymph node metastases are common, and the overall prognosis is poor, with only three of 22 patients (14%) alive and disease free at 2 years in one large series (243).
Adenoid Cystic Carcinoma
Adenoid cystic carcinoma is a rare tumor that occurs most frequently in the salivary glands but also in the respiratory tract, skin, mucous membranes of the head and neck, and the breast. In the female genital tract, it occurs in Bartholin's gland, the endometrium, and the cervix (244). Ultrastructural features of both squamous and glandular epithelium are seen, leaving the issue of the etiology of these tumors unresolved. Approximately half the tumors have associated squamous carcinoma or dysplasia (245), whereas adenocarcinoma has a less-frequent association.
These tumors usually occur in postmenopausal black women of high parity (244,246). Most present with postmenopausal bleeding, but some may be suspected by the presence of small “undifferentiated” cells on a routine Pap smear (244). Approximately half the cases are stage I at presentation, but overall survival is poor. Prempree et al. (246), in a review of the literature, reported a 3- to 5-year survival rate of only 56.3% (9 of 16) for patients with stage I disease, regardless of the type of treatment. The survival rate for stage II disease was 27.3% (3 of 11), and no patient with stage III or IV disease survived. Lung metastases are common, whereas the tumors spread locally by direct tissue invasion and perineural infiltration.
Adenoid Basal Carcinoma
This is a rare tumor with an excellent prognosis. Most adenoid basal carcinomas have coexistent in situ or invasive squamous carcinoma, and 50% have coexistent in situ or invasive adenocarcinoma (247). The disease is almost invariably confined to the cervix, and in a review of 26 cases reported in the literature, only one died of disease (with lung metastases) (248). Invasion is usually superficial, and extrafascial or radical hysterectomy without lymphadenectomy is a reasonable treatment option.
Clear Cell Adenocarcinoma
Clear cell adenocarcinoma of the cervix was rare until 1970, when the incidence rose because of its association with in utero exposure before the eighteenth week of pregnancy todiethylstilbestrol and related nonsteroidal estrogens (249). The tumor occurs in two distinct age groups: those younger than 24 years and those older than 45 years (250). The latter are unrelated to in utero diethylstilbestrol exposure, but even in young women, there is no history of hormone exposure in 25% of cases. Treatment should be similar to that for other adenocarcinomas. Unlike clear cell carcinoma of the endometrium, which carries a much worse prognosis, clear cell adenocarcinoma of the cervix has a prognosis comparable to that of other adenocarcinomas (250,251).
Villoglandular Papillary Adenocarcinoma
This uncommon lesion tends to occur in younger women and to have a more favorable prognosis. Young and Scully (252) reviewed their consultation files to report 13 cases. The patients' ages ranged from 23 to 54 years (average 33 years). Two of the patients were pregnant. Both were asymptomatic, both had a grossly abnormal-appearing cervix, and one had an abnormal Pap smear. Treatment ranged from cone biopsy for very superficial cases to radical hysterectomy and pelvic lymphadenectomy. With follow-up of 2 to 14 years, no recurrences were seen.
In the largest reported series by Jones et al. (253), none of 24 cases had lymph-vascular invasion or lymph node metastases, and all patients remained free of disease with 7 to 77 months of follow-up. A review of seven cases by Kaku et al. (254) revealed lymph-vascular invasion in two patients, both of whom had pelvic lymph node metastasis. One of the two had recurrence at 30 months and died at 46 months.
Because of their generally excellent prognosis and young age at presentation, conservative management may be justified in selected patients who want to retain fertility (253).
Small-cell cancers are a rare, heterogeneous group of tumors, representing 0.5% to 5% of all invasive cervical cancers (255). In a thorough evaluation of 2,201 invasive cervical cancers at the University of Kentucky Medical Center, Van Nagell et al. (177) noted 25 cases (1.1%) of small-cell carcinoma. They were characterized by a nuclear area of 160 µm2 or less and a maximum nuclear diameter of 16.2 µm. Thirty-three percent of the small-cell carcinomas stained positively for the neuroendocrine markers (neuron-specific enolase and chromogranin), whereas the remainder stained only for epithelial markers such as cytokeratin and epithelial membrane antigen. Both types of small-cell cancers had a higher frequency of lymph-vascular space invasion, a significantly higher rate of recurrence, particularly to extrapelvic sites, and a lower survival rate.
The neuroendocrine tumors arise from the argyrophil cells or APUD cells (amine precursor uptake and decarboxylation) in the cervix (255). None of the neuroendocrine tumors in the Kentucky series had clinical signs of a paraendocrine syndrome, although these tumors may sometimes present with carcinoid syndrome, and the patients then have elevated levels of 5-hydroxy-indoleacetic acid in the urine.
An epidemiological study using population-based data reported to the Surveillance, Epidemiology, and End Results program in the United States compared 239 cases of endocrine tumors of the cervix with 18,458 squamous cell carcinomas (256). Mean age at diagnosis was 49 years for the endocrine tumors versus 52 years for the squamous carcinomas (p <0.01). Endocrine tumors were more likely to present at a later FIGO stage (p <0.01) and to have lymph node involvement at diagnosis (57% vs. 18%, p <0.01). At all stages of disease, survival was worse for the women with endocrine tumors.
A later study reviewing SEER data from 1977 to 2003 identified 290 women (0.9%) with small-cell carcinoma of the cervix, 27,527 (83.3%) with squamous cell carcinoma, and 5231 patients (15.8%) with adenocarcinoma (257). Five-year survival for small-cell carcinoma (35.7%) was worse compared with squamous cell carcinoma (60.5%) and adenocarcinoma (69.7%). They noted that small-cell carcinomas had a predilection for nodal and distant metastases, but there was decreased survival even in early stage, node-negative patients.
Because of the small-cell carcinomas' propensity for early systemic spread, chemotherapy is usually advocated in addition to surgery or radiation therapy. The group at the Chang Gung Memorial Hospital in Taiwan administered adjuvant chemotherapy to 23 consecutive patients with stage IB to II small-cell cervical cancer who had been treated primarily with radical hysterectomy (258). Ten of 14 patients (71.4%) who received a combination of vincristine, doxorubicin, and cyclophosphamide alternating with cisplatin and etoposide had no evidence of disease during a median follow-up of 41 months, whereas only 3 of 9 (33.3%) who received cisplatin, vinblastine, and bleomycin (PVB) survived. The survival rate was 70% for patients with negative lymph nodes and 35% for those with positive nodes (p = 0.05). All patients who died of disease had extrapelvic metastases.
The group in Buenos Aires (259) reported 20 patients with neuroendocrine cervical carcinoma. Patients with stages IA2 (one) or IB1 (four) were treated by radical hysterectomy and pelvic lymphadenectomy with or without adjuvant chemotherapy, and all patients survived. Thirteen patients with stages IB2 to IVA disease received neoadjuvant chemotherapy with the quick VBP scheme (vincristine 1 mg/m2/day on day 1, bleomycin 25 mg/m2/day on days 1 to 3, and cisplatin 50 mg/m2/day on day 1, for 3 courses with 10-day intervals). Treatment was completed by 5,000 cGy whole-pelvic adjuvant radiation. Response to neoadjuvant chemotherapy was greater than 50% in 9 of 13 patients (69.4%), and complete response occurred in two of 13 patients (15.3%). When residual tumor was less than 2 cm after neoadjuvant chemotherapy, the overall survival was 58%, compared with 21% when it was greater than 2 cm (p <0.05). For patients with negative nodes, the overall survival was 72%, compared with 11% for those with positive nodes (p <0.01).
Papillary Serous Carcinoma
This tumor resembles microscopically its counterparts elsewhere in the female genital tract and peritoneum. Zhou and colleagues reported a series of 17 cases (260). There was a bimodal age distribution, with one peak occurring before the age of 40 years and the second peak after 65 years. Eight patients (47%) had a polypoid or exophytic mass, two patients (12%) had an ulcerated lesion, and no abnormality was detected in 7 patients (41%). Two tumors were stage IA, 12 were stage IB, two were stage II, and one was stage III. Seven tumors (41%) were mixed with another histologic subtype of cervical adenocarcinoma, most commonly lowgrade villoglandular adenocarcinoma. Eight patients (47%) were alive without evidence of disease with a mean follow-up of 56 months. The researchers concluded that the tumors can behave aggressively with supradiaphragmatic metastases and a rapidly fatal course when diagnosed at an advanced stage, but the outcome for patients with stage I tumors was similar to that of patients with cervical adenocarcinomas of the usual type.
A literature review by Rotmensch et al. (261) in 1983 identified 105 reported cases of cervical sarcomas. They classified them as shown in Table 9.13. A variety of therapies had been used in the management of cervical sarcomas, and the overall prognosis was poor, except for the adenosarcomas. The authors concluded that more rigid criteria for diagnosis were needed to allow evaluation of the various therapies.
In 1988, Daya and Scully (262) reviewed 13 cases of this rare tumor. The patient ages ranged from 12 to 26 years, with a mean of 18 years. All had polypoid lesions and presented with vaginal bleeding, “something” protruding from the introitus, or both. The patients were treated with a variety of operative procedures, with or without adjuvant chemotherapy, the operative procedures ranging from cervical polypectomy to hysterectomy with pelvic and paraaortic node dissection. Twelve of the 13 patients (92%) were alive and well 1 to 8 years after surgery.
Results from the Intergroup Rhabdomyosarcoma Study Group's four treatment protocols were summarized by Arndt et al. in 2001 (263). There were 151 patients entered into the four protocols, and 23 tumors (15%) arose from the cervix. The modern approach to management is conservative surgery and chemotherapy—primarily vincristine, actinomycin D, andcyclophosphamide —with or without radiation therapy. The overall 5-year survival for the 151 patients was 82%. For patients with localized embryonal botryroid tumors, there was no significant difference in 5-year survival among patients with tumors at different sites. Patients with more advanced disease should be treated initially with chemotherapy, and surgical excision should attempt to conserve the function of the bladder, rectum, vagina, and ovaries if possible (264).
Table 9.13 Classification of Cervical Sarcomas
Malignant Mixed Müllerian Tumor
There have only been 40 or so cases of this rare tumor reported in the English literature. Sharma and colleagues from the University of Iowa (265) reported five cases with a mean age of 49.6 years. Most patients presented with abnormal vaginal bleeding. Two patients had stage IB1 disease, two had stage IB2, and one had stage IVB. The four patients with disease confined to the cervix were treated with radical hysterectomy, with or without postoperative radiation, and all were alive and free of disease at 28, 35, 42, and 65 months, respectively.
Cervical lymphomas are rare. Of 9,500 women with lymphomas reported by the Armed Forces Institute of Pathology, only 6 (0.06%) had primary cervical lesions (266).
Patients usually present with abnormal vaginal bleeding, and clinically the cervix is expanded by a subepithelial mass without ulceration or fungation.
Histologic diagnosis is difficult. Harris and Scully (267) reported that only 15 of 25 cases (55%) referred for consultation were correctly diagnosed by the referring pathologist. Komaki et al. (268) emphasized the importance of distinguishing malignant lymphoma from undifferentiated carcinoma or sarcoma because cervical lymphoma can be successfully treated in spite of locally advanced disease.
Perrin et al. (269) reviewed the literature in 1992 and found 72 cases of lymphoma of the cervix or upper vagina reported since 1963. Interpretation of the data was hindered by outdated methods of histologic classification in approximately half the cases. Staging information, if given, tended to be reported according to the FIGO classification rather than according to the Ann Arbor classification used routinely in lymphoma practice.
The researchers concluded that the outcome for cervical and vaginal lymphomas was unpredictable but that excellent results could be achieved even if the tumor was high grade, bulky, or extensive. They stressed the need for thorough staging, including CT scan of the chest, pelvis, and abdomen; bone marrow aspiration; hematologic analysis; and biochemistry.
Regarding treatment, they found no evidence that radical gynecologic surgery was advantageous (269). For localized (Ann Arbor stage IE) and nonbulky disease (FIGO stage I and II) of low and intermediate grade, they recommended pelvic radiation therapy or modern combination chemotherapy. For more extensive disease (stage IIE), bulky locally advanced disease (FIGO stages III and IV), or disease of high grade, they recommended modern chemotherapy, possibly in conjunction with radiation therapy.
This slow-growing, locally aggressive, papillomatous lesion was first reported in the cervix in 1972 (270).
In a literature review in 1988, Crowther et al. (271) reported 34 cases of cervical verrucous carcinoma, although they believed that some of these should be considered papillomas that had undergone malignant change to squamous cell carcinomas. The age of the women ranged from 30 to 84 years (average 51 years), and only two had a past history of genital warts. Symptoms included vaginal discharge (42%) and abnormal bleeding (50%), whereas 35% had an abnormal Pap smear. Colposcopy was not helpful because the lesion looked like a large condyloma acuminatum. The lesions were confined to the cervix in 41% of cases, involved the vagina in 36%, and the parametrium in 23%. One case invaded the bladder.
Radical surgery is the mainstay of treatment. Radicality of surgery varied in the cases reviewed by Crowther et al. (271), but of 14 patients having radical hysterectomy (with vaginectomy in 3 cases), recurrence occurred in six (43%). Three of the recurrences were salvaged with radiation therapy or exenterative surgery. Radiation therapy was used as a primary or secondary treatment in 17 cases, and failures occurred in ten of these (59%). Anaplastic change was not noted. Lymph node metastases were found in two patients and pulmonary metastases in a third, but careful histologic evaluation at autopsy showed nests of classic squamous carcinoma cells invading the stroma in two of these cases. Overall, recurrent or persistent disease was noted in 21 of the 34 cases (62%), with 82% of relapses occurring within 8 months.
Schwade et al. (272) reported anaplastic transformation and rapid clinical deterioration following radiation therapy in 10.7% of verrucous carcinomas, but suggested that many of these lesions were large and may have already contained occult areas of squamous cell carcinoma.
Malignant melanoma of the cervix is a rare entity, and it is important to exclude a metastatic lesion. Literature reviews and case studies have been reported by Mordel et al. (273) in 1989 and Santosa et al. (274) in 1990. These tumors have in general been reported to occur in the seventh and eighth decades of life, and most lesions present with abnormal vaginal bleeding. Macroscopically, the tumors are strongly colored, polypoid masses, and most patients have FIGO stage I or II disease at diagnosis. Recommended treatment is usually radical hysterectomy with or without pelvic lymphadenectomy. Adjuvant radiation may improve local control if the surgical margins are close. The 5-year survival rate is poor, not exceeding 40% for stage I disease and reaching only 14% in stage II (273).
Metastasis of malignant epithelial tumors to the uterine cervix is a rare occurrence. Lemoine and Hall (275) reviewed the surgical pathology files of the London Hospital for the 65 years from 1919 to 1984 and found only 33 acceptable cases. Cases that involved direct extension from a primary site, such as the endometrium or rectum, were excluded. They also reviewed the literature for individual case reports and small series. Documented primary sites of diseases included stomach (25 cases), ovary (23), colon (21), breast (14), kidney (1), renal pelvis (1), carcinoid (1), and pancreas (1).
The patients almost invariably present with vaginal bleeding, and the histologic features of the cervical biopsy lead to a search for an asymptomatic primary tumor.
Cancer of the Cervical Stump
Subtotal hysterectomy is less commonly performed today than in the past, but when invasive cancer arises in a cervical stump, the principles of treatment are the same as those for an intact uterus. The technique for abdominal radical trachelectomy is essentially the same as for radical hysterectomy, the only difficulty being the maintenance of adequate traction on the stump. Sometimes the bladder may be adherent over the stump, necessitating careful dissection. The ability to deliver an adequate dose of radiation to patients with advanced disease depends on the length of the cervical canal and is compromised if the canal is less than 2 cm long. Although 5-year survival rates compare favorably to those in patients with an intact uterus, complication rates are higher because of the previous surgery and the sometimes compromised methods of radiation therapy (276).
Invasive Cancer Found after Simple Hysterectomy
When invasive cervical cancer is discovered after simple hysterectomy, the treatment options include full pelvic radiation or radical surgery consisting of radical parametrectomy, upper vaginectomy, and pelvic lymphadenectomy.
Our preference is to perform radical surgery, as long as a CT scan of the chest, pelvis, and abdomen or a PET scan shows no evidence of metastatic disease and there are no high-risk features in the hysterectomy specimen (i.e., positive surgical margins, tumor deeply infiltrating, or prominent vascular space invasion). In the presence of high-risk features, we prefer primary pelvic radiation.
The operation is considerably more difficult than a radical hysterectomy, the main difficulty being the identification of the bladder, which is usually adherent over the vaginal vault. Operating in the low lithotomy position to allow use of a metal instrument (e.g., narrow malleable retractor) to push up on the vault from below facilitates identification of the bladder boundaries. Kinney et al. (277) from the Mayo Clinic reported 27 patients undergoing reoperation. Ureterovaginal fistulas developed in two of the 27 cases (7%), but the 5-year absolute survival rate was 82%. The group at Irvine, California, reported 18 patients with a median follow-up of 72 months (278). The overall actuarial survival was 89%. Morbidity was comparable to that of patients undergoing primary radical hysterectomy.
Hopkins et al. (279) reported 92 patients who were treated by primary radiation therapy. Prognosis was similar to that for patients treated initially by radical surgery or radiation therapy for squamous lesions. Fifty-seven patients with stage I squamous cell carcinoma had a 5-year survival rate of 85%, whereas 27 patients with stage I adenocarcinoma had a 5-year survival rate of 42%. The researchers suggested that alternative approaches should be investigated for adenocarcinomas.
A study from South Korea reported 64 patients who were treated by primary external beam radiation therapy or intracavitary radiation (280). Overall 5-year survival was 75.8%. For patients in retrospect stages IA, IB, and IIB (gross residual after surgery), overall 5-year survival rates were 90.9%, 88.8%, and 27.9% respectively.
A study from Chandigarh, India, reported 105 patients who were found to have invasive cervical cancer following total (n = 82) or subtotal (n = 23) hysterectomy (281). All patients were treated with external beam radiation, with or without intracavitary radiation. The 5-year overall survival, disease-free survival, and pelvic control rates for all patients were 55.2%, 53.3%, and 72%, respectively. Adverse prognostic factors included absence of brachytherapy, hemoglobin <10 g%, and interval between surgery and radiation >80 days.
Coexistent Pelvic Mass
A pelvic mass may be identified clinically or on a staging CT scan of the pelvis and abdomen. Solid masses of uterine origin are usually leiomyomas and do not need further investigation.
If the preferred treatment is radiation, any coexistent pyometra or hematometra must be drained, using ultrasonic guidance if necessary. Repeated dilatation of the cervix and aspiration of pus may be necessary every 2 to 3 days if there is ultrasonic evidence of a further collection. Broad-spectrum antibiotics should be used to cover Bateroides, anaerobicStreptococcus, and aerobic coliforms. Active infection decreases the response to radiation and may be exacerbated into a systemic infection if brachytherapy rods are packed into the uterus.
Coexistent adnexal masses must be explored and a histologic diagnosis obtained. A laparoscopic approach may be appropriate if the risk of malignancy is low. Benign adnexal masses can be surgically excised. Inflammatory masses can be excised and an omental carpet used to prevent bowel adhesions. Malignant masses require surgical staging or cytoreductive surgery, depending on the individual case.
Torrential bleeding may occasionally follow biopsy or pelvic examination, particularly with friable, advanced cancer. A wide gauze bandage, soaked in Monsel's solution (ferric subsulfate) and tightly packed against the cervix, usually controls the bleeding. It should be changed after 48 hours. If control of the bleeding is not achieved, then consideration should be given to embolization of the hypogastric or uterine arteries (282), although this approach may increase tumor hypoxia, thereby decreasing radiosensitivity.
Commencement of external-beam therapy controls the bleeding within a few days. Daily fractions may be increased to 300 to 500 cGy for 2 or 3 days, or transvaginal orthovoltage treatment may be given if a suitable machine is available.
Recurrent Cervical Cancer
Treatment of recurrent disease depends on the mode of primary therapy and the site of recurrence. If the disease recurs in the pelvis after primary radiation therapy, most patients require some type of pelvic exenteration (see Chapter 22), although an occasional patient may be salvaged by radical hysterectomy.
Eifel et al. investigated the time course of central pelvic recurrence in 2,997 patients treated with radiation therapy for stages I and II squamous cell carcinoma of the cervix at the M.D. Anderson Cancer Center in Houston, Texas (283). Recurrence rates were 6.8%, 7.8%, and 9.6% at 5, 10, and 20 years, respectively. The risk of central pelvic recurrence was independently correlated with tumor size (p <0.0001) but not with FIGO stage. Although after 3 years the risk of central recurrence was low, it continued to be slightly greater for patients with tumors ≥5 cm than for those with smaller tumors (p = 0.001). Patients with recurrence after 36 months had a significantly better survival following salvage therapy.
With pelvic recurrence after primary surgery, radiation therapy is the treatment of first choice. Grigsby reported 36 patients who received external beam and brachytherapy for recurrent cervical cancer following radical hysterectomy (284). Tumor was recurrent in the central pelvis in 33 patients (92%) and on the pelvic sidewall in three cases. The overall 5- and 10-year survivals were 74% and 50%, respectively. Ten patients (28%) developed a further recurrence after irradiation, and seven (70%) of these had a pelvic component to the failure. Severe complications developed in four patients (11.1%), including one hip fracture, one bowel obstruction requiring a colostomy, and two fistulae. Using radiation with concurrent chemotherapy (5-fluorouracil with or without mitomycin C), Thomas et al. reported eight of 17 patients (47%) alive and disease free 21 to 58 months after therapy. The recurrent disease was present in the pelvis alone or pelvis and paraaortic nodes, and seven of the eight survivors had a component of pelvic sidewall disease (285).
Pulmonary metastases following primary radical hysterectomy have been reported in 6.4% of patients (24 of 377) with negative pelvic nodes and 11.3% of patients (16 of 142) with positive pelvic nodes (286). When the lung was the only site of recurrence, a 5-year survival of 46% was achieved by surgical resection followed by chemotherapy in 12 patients who initially had negative pelvic nodes and who now had one to three pulmonary metastases. Surgery was performed in the presence of unilateral or bilateral metastases.
Radical Hysterectomy for Recurrence
Selected patients with limited persistent or recurrent disease in the cervix after primary radiation therapy may be suitable for radical hysterectomy, with or without partial resection of bowel, bladder, or ureter. The morbidity rate is high, but some patients can be cured without the need for a stoma.
Rutledge et al. (287) from London, Ontario, reported data on 41 patients who underwent conservative surgery for postradiation recurrent or persistent cervical cancer. Thirteen patients who initially had FIGO stage IB or IIA disease underwent radical abdominal or radical vaginal hysterectomy. The 5-year survival rate for this group was 84%, and major morbidity occurred in 31% of cases. A second group of 20 patients had more advanced initial disease, and all underwent radical abdominal hysterectomy. This group had a 49% 5-year survival rate and a major morbidity rate of 50%. A third group of eight patients required an extended Wertheim's operation to encompass locally advanced disease involving the bladder base or parametrium. This group had a 5-year survival rate of 25% but experienced a 75% rate of major morbidity, including two treatment-related deaths. Fistula formation occurred in 26% of patients overall.
An Italian study of 34 patients reported an actuarial 5-year survival of 49% for the whole group, with major complications in 44% of cases and a fistula rate of 15% (252). Patients with FIGO stage IB-IIA disease at primary diagnosis, no clinical parametrial involvement, and small (≤4 cm) tumor diameter at the time of recurrence had a survival of 65% (11 of 17).
It would appear that conservative surgery is realistic only for patients with small disease confined to the cervix, preferably detected on biopsy 4 to 6 months after primary radiation for bulky stage IB or IIA cervical cancer.
Patients with recurrent or metastatic cervical cancer are commonly symptomatic and may experience pain, anorexia, weight loss, vaginal bleeding, cachexia, and dyspnoea, among other symptoms. The role of chemotherapy in such patients is palliation, with the primary objective to relieve symptoms and improve quality of life. A secondary objective is to prolong survival.
Many factors influence the likelihood of response to chemotherapy, and these include performance status, patient age, histological subtype, site of recurrence (lung vs. pelvis), number of metastatic sites, previous radiotherapy or chemotherapy, and the interval from initial radiotherapy or chemoirradiation (289,290). These factors should be taken into consideration when making treatment decisions because they can all influence the choice of treatment as well as the response rate.
A number of chemotherapic agents have activity in patients with metastatic cervical cancer, and the response rates for single agents are summarized in Table 9.14 (291). These studies span the last 20 years and are a composite of many trials that included very different patient subsets, making interpretation difficult. In general, the most active single agents include cisplatin, paclitaxel, topotecan, vinorelbine, gemcitabine, and ifosfamide (289,290,292,293).
Table 9.14 Single Conventional Agent Chemotherapy in Cervical Carcinoma
Cisplatin is the single most active agent for squamous cell carcinoma, and its preferred dose and schedule of administration is 50 mg/m2 every 3 weeks, intravenously (291). Although the response rate is higher with 100 mg/m2 (31.4% ) than 50 mg/m2 (20.7%), this is achieved at the cost of significant toxicity, and there is no difference in response duration, progression-free interval, or overall survival (294). The duration of response remains disappointing (4 to 6 months).
The response rates with combination chemotherapy are generally double that seen with single agents, although the majority of responses are partial and of short duration (4 to 6 months) (289,290,292,293). Long-term remissions occasionally occur, and anecdotally we have seen three long-term durable complete responses (>10 years): one in a patient with multiple pulmonary metastases, one in a patient with a supraclavicular lymph node metastasis diagnosed on fine-needle aspiration cytology, and, most unusually, one in a patient with a pelvic recurrence after neoadjuvant chemotherapy and radiation who presented with a large fixed pelvic recurence with almost complete obstruction of the rectum and was not suitable for exenteration. The first two patients were treated with single agent cisplatin and carboplatin and the third with carboplatin and paclitaxel. Interestingly, the group from Memorial Sloan Kettering recently reported three cases of recurrent metastatic cervical cancer in which the patients remain disease free many years after completing salvage chemotherapy and surgery (295).
A large number of phase II studies and a smaller number of phase III studies have investigated a variety of cisplatin-based combinations in the treatment of patients with metastatic cervical cancer, and these have been reviewed by several authors (289,290,292). There has also been a recent systematic review of all the randomized trials (293). Response rates or time to progression are traditionally the end points of phase II studies whereas progression-free survival and overall survival are the primary end points of phase III trials. Relatively few studies in the past incorporated quality of life as an endpoint, but this is now recognized as an important measure and should be included in all phase III trials.
Response rates as high as 75% have been reported with some combinations in phase II trials. On average, the median progression-free survival has been 6 to 8 months (289,290,292). The combination regimens have generally included cisplatin in addition to one or two other agents. Long has recently reviewed the published literature on the activity of thesecisplatin doublets, triplets, and four-drug regimens and concluded that, although response rates were doubled and progression-free survival was also increased, this was not associated with any prolongation of overall survival in most studies (289).
There have been very high response rates reported with three drug regimens, but these high response rates have not been confirmed in randomized trials. For example, the combination of bleomycin, ifosfamide, and cisplatin was reported to have a response rate of 69% and a median survival of 10 months in a phase II study of 49 patients (296). However, when the GOG compared this regimen with cisplatin and ifosfamide, the response rates were the same in both arms (approximately 32%), which is in the same range as that achieved with cisplatin alone (297).
The most active doublet regimens include cisplatin in combination with paclitaxel, gemcitabine, vinorelbine, or topotecan. The GOG reported data on cisplatin and paclitaxel as first-line therapy for advanced and recurrent squamous cell carcinoma (298). Of 41 evaluable patients, five (12.2%) had a complete response and 14 (34.1%) had a partial response, for an overall response rate of 46.3%. The median progression-free interval was >5.4 months (range of 0.3 to >22 months), with a median survival of >10.0 months (range 0.9 to 22.2 months). Response rates were higher in patients with disease in nonirradiated sites (70% vs. 23%; p = 0.008), a common finding in many studies.
The combination of cisplatin and gemcitabine has also been reported to have a particularly high response rate. Cisplatin was administered as an i.v. infusion on day 1 (70 mg/m2), and gemcitabine was administered as an i.v. infusion over 30 minutes on days 1 and 8 (1,250 mg/m2) in a 21-day cycle (299). Forty patients who either had previous pelvic radiation or were stage 4 at presentation were evaluable, and the authors reported that three of 40 (7.5%) had a complete response, 27 of 40 (67.5%) a partial response, and five of 40 (12.5%) had stable disease. Five of 40 (12.5%) progressed on treatment. The median time to progression was 8.3 months, and the median survival was 9.6 months. Thirty percent of the patients were alive at 12 months.
The GOG reported a phase II study of cisplatin and vinorelbine in 73 patients with advanced or recurrent squamous cell carcinoma of the cervix (300). The initial doses administered were cisplatin 75 mg/m2 every 4 weeks and vinorelbine 30 mg/m2 weekly. The overall response rate was 30% (5 complete and 15 partial responses). The overall median response duration was >5.5 months. The major toxicity was neutropenia: 16% grade 3 and 67% grade 4. Gastrointestinal and neurotoxicity were infrequent and mild.
Fiorica et al. reported a phase II trial of cisplatin and topotecan as first-line therapy for patients with persistent or recurrent squamous and nonsquamous cervical cancer (301). There were 32 evaluable patients, and the overall response rate was 28% (9 of 32), with three complete responses (9%). Response rates were the same in irradiated and nonirradiated tissues. Median duration of response was 5 months (range 2 to >15 months), and the median survival was 10 months.
The current GOG study 204 compares the doublets paclitaxel, topotecan, vinorelbine, and gemcitabine in combination with cisplatin, and will determine which, if any is superior.
The two most important contemporary phase III studies have been carried out by the GOG. One compared cisplatin alone with paclitaxel and cisplatin and the other comparedcisplatin alone with topotecan and cisplatin.
GOG 169 compared cisplatin and paclitaxel with cisplatin alone in 280 patients with stage IVB, recurrent, or persistent squamous cell carcinoma of the cervix (302). The patients were randomized to receive either cisplatin 50 mg/m2 or cisplatin 50 mg/m2 and paclitaxel 135 mg/m2 every 3 weeks for six cycles, There were 234 patients eligible for response. Importantly, over 90% of all patients had prior radiation therapy. Objective responses occurred in 19% of patients receiving cisplatin (6% complete plus 13% partial), versus 36% (15% complete plus 21% partial) receiving cisplatin and paclitaxel (P = .002). The median progression-free survivals were 2.8 and 4.8 months, respectively, for cisplatin versus the combination (P <.001). There was no difference in median survival (8.8 months v 9.7 months). Grade 3 to 4 anemia and neutropenia were more common in the combination arm. The GOG concluded that the combination of cisplatin and paclitaxel was superior to cisplatin alone with respect to response rate and PFS with sustained quality of life.
Carboplatin and paclitaxel is a more attractive combination from the point of view of toxicity and ease of administration and although phase II studies have demonstrated that it is a very active regimen (303,304), this has not been confirmed in randomized trials.
GOG 179 demonstrated the superiority of cisplatin and topotecan over cisplatin alone in a study of 356 patients with stage IV, recurrent, or persistent cervical cancer (305). Patients were randomized to one of three treatment arms: single agent cisplatin 50 mg/m2 every 3 weeks (n = 146), topotecan 0.75 mg/m2 on days 1-3 plus cisplatin 50 mg/m2 on day 1 every 3 weeks (n = 147), or methotrexate plus vinblastine plus doxorubicin plus cisplatin (MVAC) every four weeks.The MVAC arm was closed prematurely because of excessive toxicity. Nearly 80% of patients had received radiotherapy, and almost 60% had received cisplatin-based chemotherapy before randomization.
Objective responses were achieved in 39 of 147 patients (27%) on the combination, compared with 19 of 146 (13%) treated with single-agent cisplatin (p = 0.004). There were 14 complete responses observed with the combination (10%) compared with 4 (3%) with the single agent. Median progression-free survival for the combination was 4.6 months versus 2.9 months (p = 0.014), and median overall survival for the combination was 9.4 months versus 6.5 months (p = 0.017). Fifty seven percent of patients had been previously treated with cisplatin based chemoradiation. The median survival for patients who received no prior cisplatin was 15.4 months for the combination of topotecan and cisplatin compared to 7.9 months for those who had prior cisplatin chemoradiation. The probability of survival increased for both treatment groups the longer a patient was from prior cisplatinchemotherapy.
This is the only study to date that has reported an overall survival advantage with combination chemotherapy. The authors concluded that topotecan and cisplatin should be considered the standard of care for patients with advanced or recurrent cervical cancer. Quality of life scores were similar in the two arms of the study.
With increasing numbers of patients being treated with concurrent chemoradiotherapy with cisplatin as primary treatment, there is a need to develop new active non-cisplatin based combinations, as response rates to further cisplatin-based chemotherapy in these patients are much lower than in previously untreated patients. There have only been a few studies to evaluate non-cisplatin containing doublets in patients who have received cisplatin as part of their primary therapy and who have relapsed within 12 months. There are a number of possible agents that could be combined, and they include any of the active single agents discussed above. In a phase II study of topotecan and paclitaxel for recurrent, persistent, or metastatic cervical cancer, a New York group reported 7 responses (54%) among 13 evaluable patients (1 complete, 6 partial) (3). Progression-free and overall survivals were 3.8 and 8.6 months, respectively.
The role of targeted therapies in cervical cancer is at present unknown, but there is a strong theoretical rationale to support such studies, and this is an area of active research. For example, EGFR-1 is highly expressed in primary and recurrent cervical tumors and drugs such as cetuximab may be of benefit (307). Bevacuizimab has shown activity in combination with fluorouracil in a small number of heavily pretreated patients and should also be investigated further (308). The GOG are investigating cetuximab and cisplatin (GOG 0076DD) as well as the activity of erlotinib (GOG 0277D) and bevacizumab (GOG 0277C) in patients with metastatic cervical cancer, and the results of these studies will influence the next generation of cervical cancer trials.
Ultimately, the approach to management and the choice of treatment is influenced by multiple factors. These include the age and performance status of the patient, the site of recurrence, the time to recurrence, the patient's symptoms, the number of metastatic sites, prior therapy including chemoradiation, and the pace of the disease. Chemotherapy for metastatic cervical cancer is generally disappointing, and, despite higher response rates with combination chemotherapy, the duration of response is relatively short in the majority of patients.
The objective of treatment is to palliate symptoms and improve quality of life. Ideally, eligible patients should be enrolled into clinical trials. However, in the absence of appropriate trials, it is our practice to use platinum-based combinations such as cisplatin and topotecan or carboplatin and paclitaxel or gemcitabine in patients with a good performance status. We would consider single agents such as carboplatin alone or weekly cisplatin in patients with a poorer performance status.