INTRODUCTION Approximately 9710 women will be diagnosed with cervical cancer in 2006, resulting in 3700 deaths. This represents 0.13 percent of all cancer deaths in women. Squamous cell carcinoma (SCC) accounts for approximately 80 percent of cervical cancers, adenocarcinoma for 15 percent, and adenosquamous carcinoma for 3 to 5 percent. In addition, neuroendocrine or small cell carcinomas can infrequently originate in the cervix. Management of women with nonmetastatic invasive cervical SCC depends upon the FIGO stage of disease at diagnosis. OVERVIEW OF TREATMENT OPTIONS There are several options for treatment of early stage (FIGO IA, IB1, nonbulky IIA, cervical cancer:
The optimal choice depends upon the patient's age and childbearing plans, disease stage, whether comorbidities are present, whether histopathological review of surgical specimens reveals characteristics associated with an increased risk of recurrence, and physician and patient preference. Radical hysterectomy plus pelvic/paraaortic lymphadenectomy and definitive RT are equally effective, but differ in associated morbidity and type of complications. Advantages of surgery over primary RT for young women are that the ovaries can be left intact, and the sexually active patient may be left with a more functional vagina. If the need for adjuvant RT is anticipated, the ovaries can be transposed out of the radiation field. Primary surgery also allows for the resection of bulky metastatic lymph nodes, which may be of therapeutic benefit. On the other hand, if a primary surgical approach is chosen and adjuvant chemoradiotherapy is required, there may be additional morbidity from this multimodality approach, as compared to definitive chemoradiotherapy. Radical hysterectomy Piver described five types of radical hysterectomy depending upon the extent of dissection. The therapeutic efficacy of a type II radical hysterectomy appears comparable to that of a type III procedure for stage IB and IIA cervical cancer, but with lower morbidity. A randomized trial directly compared type ll (modified radical hysterectomy) and type lll (radical hysterectomy) procedures in patients with stage lB or llA disease. The type II operation was associated with a shorter mean operative time (135 versus 180 minutes), less late urologic morbidity (13 versus 28 percent), and similar recurrence rates (24 versus 26 percent), cause-specific mortality (18 versus 20 percent), five year overall survival (OS, 81 versus 77 percent) and five year disease-free survival (DFS, 75 versus 73 percent). Thus, the type II procedure appears preferable as long as appropriate tumor clearance can be achieved. Even if a type III radical hysterectomy is performed, it is rarely necessary to remove as much vagina as Piver initially recommended to achieve tumor clearance. Complications of radical hysterectomy and details of the procedure are discussed separately. Laparoscopy-assisted radical vaginal hysterectomy (LARVH) may be considered in selected patients. Advantages of this approach include less blood loss, better cosmetic results, faster recovery, and shorter hospitalization. The efficacy of LARVH was shown in a series of 200 women with FIGO stage IA1 L1 (lymphatic vessel, or lymphovascular invasion) to IIB cervical cancer. The surgical approach consisted of laparoscopic visualization of the abdominal cavity to exclude macroscopic disease, followed by laparoscopic lymphadenectomy, and radical vaginal hysterectomy (type II or III). In this series, pelvic lymphadenectomy was performed in all cases and paraaortic lymphadenectomy in 85 percent. Additionally, sentinel node biopsy was undertaken in 60 patients and correlated with findings of lymphadenectomy. The projected five-year overall survival was 83 percent with a median follow-up of 40 months. This is comparable to expected five-year survival rates following an abdominal approach. Similar to previous studies, poor prognostic factors included advanced tumor stage/size, the presence of lymph node metastases, and the combination of lymphovascular and angiovascular space involvement; however, lymphovascular space invasion alone did not influence outcome The complication rates in this series were similar to those seen with abdominal surgery and in general, declined over time. This was especially noted for bladder and ureteral injuries and likely explained by a learning curve for mastering the procedure. Severe complications were infrequent and included conversion to an abdominal approach in one patient due to the development of severe renal vein bleeding during infrarenal lymphadenectomy. Given similar survival and reasonable complication rates, the authors concluded that patients with tumors less than 4 cm, negative lymph nodes, and the absence of lymphovascular and angiovascular space involvement could be safely identified by laparoscopic staging and managed by LARVH. Several other observational studies support these conclusions; however, there are no data from randomized studies. Lymphadenectomy A primary surgery approach to treatment of cervical cancer allows (1) resection of bulky lymph node metastases, which may be of therapeutic benefit, and (2) thorough staging lymphadenectomy, which enables individualization of the RT field if histopathological review of surgical specimens indicates postoperative chemoradiotherapy might be useful The necessity for, and extent of lymphadenectomy depends upon disease stage.
Sentinel node biopsy According to the sentinel lymph node (SLN) hypothesis, tumor cells migrating from a primary tumor colonize one or a few lymph nodes before involving other nodes. Peritumoral injection of technetium-99 radiocolloid and/or a vital blue dye permits identification of one or more SLNs in the majority of patients, and its status accurately predicts the status of the remaining regional LNs. While SLN mapping and biopsy is an accepted procedure for cutaneous melanomas involving the vulva, its reliability for clinical use in the treatment of early stage cervical cancer has not yet been established Fertility-preserving surgery Randomized trials are not available that directly compare outcomes of fertility preserving surgery versus radical hysterectomy for treatment of early stage cervical cancer. However, observational series support the view that women who strongly desire to retain fertility may be treated successfully without a hysterectomy. Conization for stage IA1 disease Conization is an acceptable therapeutic alternative to hysterectomy in a young woman desirous of maintaining fertility, if the depth of invasion is less than 3 mm, if there is no lymphovascular invasion, and if the margins and endocervical curettage are negative for dysplasia. Lesions with a depth of no more than 3 mm have a 1 percent or less risk of LN metastasis. By comparison, when the depth of invasion is 3.1 to 5 mm, nodal metastases are present in up to 8 percent, and this approach should not be pursued. If the endocervical conization margin or endocervical curettings are positive, repeat conization should be performed to exclude more deeply invasive residual disease. The importance of the conization margin was demonstrated in one report in which the presence of dysplasia either at the endocervical conization margin or in the endocervical curettings was a strong predictor of residual invasive disease. The observed incidence of residual invasive disease was 4 percent when both were negative compared to 33 percent when both were positive. A positive endocervical conization margin carried a 22 percent risk for residual invasive disease, regardless of the endocervical curettage specimen. Lymphovascular space invasion is reported to be present in more than 10 percent of cases of stage IAI disease. The significance of lymphovascular invasion is not well documented, and it is not included in the FIGO staging definitions. However, lymphovascular invasion has been associated with lymph node metastases in some reports. As an example, in one study the risk of nodal involvement for patients with and without lymphovascular invasion was 32 versus 0 percent, respectively. Radical trachelectomy for stage IA2/IB1 disease Radical trachelectomy with lymphadenectomy is an alternative to radical hysterectomy for selected women with early stage lesions who wish to preserve fertility. With this procedure, the cervix and parametria are resected with placement of a cerclage so that the uterus can be preserved with a competent vaginal-uterine junction. Radical trachelectomy can be performed transvaginally or transabdominally and combined with a laparoscopic or open diagnostic/therapeutic lymphadenectomy. In one GOG study, however, laparoscopic aortic lymphadenectomy was found to be more complete than laparoscopic pelvic lymphadenectomy Radical trachelectomy is a reasonable approach for highly selected young women with stage IA2 or small stage IB1 disease for whom fertility preservation is an issue. Frequently used selection criteria include lesion size less than 2 cm, absence of overt LN metastases, and absence of vascular/lymphatic space involvement, but these have not been consistent in all reports. The optimal preoperative evaluation for selecting patients meeting these criteria has also not been determined. Although experience with this procedure is limited, it appears to result in a similar oncologic outcome as radical hysterectomy and allows for the possibility of future pregnancy, as illustrated by the following studies:
The most common intraoperative complications were vascular and urinary tract trauma; postoperative complications included inability to void, vulvar edema and hematomas, and lymphedema. Ten to 17 percent of planned procedures were abandoned because disease was more extensive than anticipated.
Although indications for adjuvant therapy after radical trachelectomy have not been defined, it should be considered for women with positive lymph nodes, positive/close resection margins, lymphovascular invasion, or deep stromal invasion. Women are advised to wait six to 12 months after the procedure before attempting to conceive, although this interval is not based on any data. Close follow-up for signs of cervical insufficiency is indicated during pregnancy. INDICATIONS FOR ADJUVANT THERAPY High-risk disease Women with one or more of the following findings are considered to be at high risk for recurrent disease, and should receive adjuvant therapy following hysterectomy:
Although there is a positive correlation between the number of positive nodes and the risk of recurrent disease , even one microscopically positive node may convey the same recurrence risk as several positive nodes, and should prompt consideration of adjuvant chemoradiotherapy RT versus chemoradiotherapy The superiority of concomitant chemoradiotherapy over adjuvant RT alone was shown in a trial that randomly assigned 268 women with high-risk but localized cervical cancer following radical hysterectomy to RT (49.3 Gy in 29 fractions to a standard pelvic field) with or without chemotherapy (four cycles of cisplatin 70 mg/m2 on day one, plus 5-fluorouracil [5-FU] 1000 mg/m2 per day by continuous infusion for four days, every three weeks) . The first and second courses were administered concurrent with RT. The use of chemotherapy was associated with a significantly better four year overall survival (81 versus 71 percent) and progression-free survival (PFS, 80 versus 63 percent). Patients who completed three to four cycles of chemotherapy had significantly better outcomes than those who only completed one or two courses, suggesting additional benefit from adjuvant chemotherapy after completion of concomitant chemoradiotherapy.The benefits of chemoradiotherapy over RT alone were further confirmed in a Cochrane meta-analysis that included 24 trials in which women with FIGO stage IB to IVA disease were randomly assigned to primary therapy with concomitant chemoradiotherapy versus RT with or without surgery, and with or without additional adjuvant chemotherapy. Although there was some evidence of statistical heterogeneity, the major findings were:
Although weekly cisplatin during radiotherapy has been studied in advanced stage but not early stage disease, this approach is often preferred due to its more favorable toxicity profile compared to cisplatin and 5-FU. When weekly cisplatin is used, randomized trials of chemoradiotherapy in cervical cancer (similar to those in head and neck cancer) suggest that achieving a total cisplatin dose of 200 mg/m2 is an important threshold for beneficial antitumor effectsThe impact of anemia on outcomes from chemoradiotherapy and controversies regarding the use of recombinant erythropoietin and red cell transfusion in this setting are presented elsewhere.Intermediate-risk disease The benefit for postoperative RT in women with factors suggestive of intermediate-risk disease was demonstrated in a GOG trial that randomly assigned 277 such women to pelvic RT (without chemotherapy) or no further postoperative treatment. The features that were considered indicative of intermediate risk-disease in this study were as follows (show table):
In the early report, adjuvant RT was associated with a significant improvement in two-year recurrence-free survival (88 versus 79 percent), and despite early follow-up, a significant 36 percent reduction in the risk of death. In a later publication with 10-year median follow-up, a significant benefit was still evident for RT in terms of progression-free survival (hazard ratio [HR] 0.58, 95% CI 0.40 to 0.85), but the 30 percent reduction in the risk of death was of borderline statistical significance (p = 0.07. Chemoradiotherapy versus RT alone Unfortunately, there are no randomized trials that specifically address the benefit of chemoradiotherapy versus RT alone in women with intermediate-risk early stage cervical SCC. Some information regarding the impact of tumor size on the benefit of chemoradiotherapy versus RT alone is available from a secondary analysis of the previously described trial (GOG 109) of postoperative RT versus chemoradiotherapy in women undergoing radical hysterectomy and pelvic lymphadenectomy for stage IA2, IB or IIA cervical cancer. The absolute improvement in five-year survival from the addition of chemotherapy to RT appeared to be less for tumors 2 cm (82 versus 77 percent, difference of 5 percent) than it was for those over 2 cm (77 versus 58 percent, difference of 19 percent) , and for patients with only one nodal metastasis compared to more than one. These data support the view that smaller tumors appear to derive quantitatively less benefit from the addition of chemotherapy to RT. Nevertheless, women who have different stages of cervical cancer all appear to benefit from the use of concurrent chemoradiotherapy, and while there may be differences in the magnitude of benefit, there is likely to be a continuum of benefit as demonstrated by the secondary analysis of GOG 109, described above. In the absence of data from randomized controlled trials, it seems reasonable to extend the concept of concomitant chemoradiotherapy to medically fit patients with intermediate risk factors for recurrence, although this approach is not universally accepted . In its most recent protocol, which incorporates adjuvant postoperative RT for women with invasive cervical cancer (GOG trial 201), the GOG recommends concomitant chemoradiotherapy for women with both intermediate-risk and high-risk disease. DEFINITIVE RT Definitive RT and radical surgery are both accepted treatments for stages IA, IB, and IIA cervical cancer, since oncologic outcomes are similar . In the only randomized trial directly comparing hysterectomy plus adjuvant RT versus RT alone for women with stage IB1 to IIA disease, five-year rates of overall survival and DFS were identical in both groups (83 and 74 percent, respectively) . The choice of treatment depends upon the treating institution, the preference of the treating oncologists, and the patient's general condition. Patients who undergo definitive RT alone should also receive concomitant cisplatin-based chemotherapy. The superiority of concomitant chemoradiotherapy over RT alone in women with both early and locally advanced cervical cancer has been shown in at least five controlled trials and a meta-analysis. These data have led to the adoption of chemoradiotherapy as the preferred approach whenever RT is administered for the treatment of women with cervical cancer, over a broad spectrum of disease stages. RT techniques The two main methods of radiation delivery for cervical cancer are external photon beam RT and brachytherapy, which can be delivered using an intracavitary approach with a variety of applicators, or via an interstitial approach using needles or afterloading catheters. Although intracavitary brachytherapy alone is adequate treatment for stage IA1 disease, external beam RT is generally added to brachytherapy to improve pelvic control with more advanced disease. Intracavitary brachytherapy is the most commonly used technique . Interstitial brachytherapy is typically considered for women whose disease cannot be optimally encompassed by intracavitary application. Some published reports suggest inferior outcomes with interstitial as compared to intracavitary brachytherapy in similarly staged patients . This was illustrated in a retrospective series which compared outcomes in 61 patients with stage II (bulky), III, or IVA cervical cancer treated at one institution with combined external beam RT and intracavitary brachytherapy versus 70 similarly staged women treated at a second institution with external beam RT and interstitial brachytherapy. Worse outcomes were found in women treated with interstitial therapy in terms of five-year DFS (21 versus 50 percent p=0.01) and local-regional control (32 versus 61 percent, p=0.01). Rates of serious long-term morbidity were similar in both groups (about 21 percent). Thus, interstitial brachytherapy should be used only in select cases in which the use of intracavitary radiation is precluded. More promising results were reported using a hybrid low-dose rate (LDR) interstitial/intracavitary technique in a series of 185 women with stage IB to IV disease. Five-year DFS rates were 67, 49, and 17 percent (for stage II, III, and IV disease, respectively), and the grade 3 or 4 late complication rate was only 10 percent. However, the five-year DFS rate for women with stage IB disease was inferior (65 percent) to that expected based upon historic experience (80 to 90 percent). The American Brachytherapy Society (ABS) has published guidelines for the use of brachytherapy as a component of cervical cancer treatment. The administered dose and application technique depends upon the initial disease volume, ability to displace the bladder and rectum, degree of tumor regression during external beam irradiation, anatomy/geometry of the area, and institutional practice. Several isotopes are available for intracavitary brachytherapy. Although low dose rate (LDR) therapy, typically with 137-Cs, is the traditionally used approach, acceptance of high dose rate (HDR) therapy, typically with 192-Ir, is increasing worldwide. HDR brachytherapy provides the significant advantage of eliminating exposure of medical personnel to radiation, a shorter treatment period, and the possibility of ambulatory treatment. In at least three randomized trials in women with cervical cancer, HDR was comparable to LDR brachytherapy in terms of oncologic outcomes and complication rates. As noted above, LDR brachytherapy alone with intracavitary 137-Cs is adequate therapy for stage IA disease while the addition of external beam RT to brachytherapy provides better outcomes for women with stage IB and IIA disease, both in terms of local control and overall survival. The use of external beam RT prior to brachytherapy for more advanced disease offers several advantages. The decreased size of bulky endocervical tumors allows more optimal coverage by the intracavitary dose distribution, while shrinking bulky exocervical disease improves tumor geometry and therefore optimal brachytherapy placement. With combined therapy, the average five-year overall survival rates for women with stage IB disease are 86 to 92 percent, and for IIA disease, 75 percent. The treatment volume for women undergoing adjuvant external beam RT typically involves the whole pelvis, with larger portals required for higher stage (ie, IIA) disease. Extended field RT, in which the treatment portal is extended to the paraaortic region, is typically considered for women who are known to or suspected of harboring paraaortic LN metastases, typically those with more advanced stage disease Complications Potential complications of brachytherapy and external beam pelvic RT, the frequency and severity of which are both field and dose-dependent, are summarized in the table (show table). The frequency of major complications from RT is 3 to 5 percent for women with stage I and IIA disease, compared to 10 and 15 percent for those with stage IIB and III disease, respectively . A second malignancy may develop following RT for cervical cancer. In an international collaborative study which included data from 15 cancer registries and 182,040 women treated for cervical cancer, a significantly increased relative risk 10 or more years after RT was observed for bladder (relative risk [RR] 2.8), rectal (RR 1.7) and other genital cancers (RR 3.1). However, the absolute risk remains low with an excess of 410 cases observed out of a total 82,616 women (0.4 percent). Ovarian transposition Woman who undergo pelvic RT will develop premature ovarian failure. Ovarian transposition has been performed in an attempt to move the ovaries out of the field of radiation, but is often unsuccessful. Furthermore, modifying standard radiation fields to shield the transposed ovaries may result in treatment failures just above the RT field. ( See "Ovarian failure due to anticancer drugs and radiation" section on Oophoropexy).Other options for preservation of fertility are discussed separately. SURGERY VERSUS RT As discussed above, definitive RT and radical surgery are both accepted treatments of early stage cervical cancer, since oncologic outcomes are similar. Therefore, the decision to proceed with one versus the other is based on other factors, such as childbearing plans, comorbidities, physician and patient preference, and quality of life (QOL) issues. In general, QOL measures in cancer survivors appear to be higher following surgery than RT; however, it is difficult to draw firm conclusions from the available data due to methodological differences . Ovarian function is more likely to be preserved with surgery than RT, providing a benefit to premenopausal patients. However, some women will develop premature ovarian failure as a result of hysterectomy, even without RT. ( Primary surgery also allows for resection of bulky lymph node metastases, which may be of therapeutic benefit, thorough staging lymphadenectomy, and it enables the selection of patients for postoperative chemoradiotherapy based upon histopathological review of surgical specimens Sexual function and psychosocial well-being Both hysterectomy and RT can lead to changes such as vaginal shortening and decreased vaginal lubrication, which adversely influence sexual function, overall QOL, and psychosocial well-being following treatment . The reported frequency with which these changes occur is quite variable, ranging from 4 to 100 percent for vaginal shortening, and 17 to 58 percent for reduced lubrication. Women should be asked about the presence of these changes and their effects; most patients respond positively to a suggestion for counseling about sexual and psychosocial issues surrounding their cancer and its treatment. Vaginal changes after RT include foreshortening, stenosis, and decreased lubrication. These physical changes impact sexual function because they can result in dyspareunia, and influence sexual satisfaction, the ability to have an orgasm, and coital frequency.
Sexual dysfunction can also occur following radical hysterectomy, and may also persist long-term
Many of the studies reporting sexual dysfunction include patients who were treated with both modalities, making it difficult to sort out the relative contribution of changes from each treatment.
Summary For women with stage IA, IB1 and nonbulky IIA cervical squamous cell cancers (SCCs), cure is possible with either radical hysterectomy or definitive RT. We generally prefer surgery, particularly for premenopausal women, for the following reasons:
If definitive RT is chosen over radical hysterectomy, concomitant cisplatin-based chemotherapy should be administered. PROGNOSIS The major prognostic factors affecting survival among women with cervical SCC are stage, nodal status, tumor volume, depth of cervical stromal invasion, lymphovascular space invasion (LVI), and, to a lesser extent, histologic type and grade. Disease stage is the most important prognostic factor, followed by lymph node status. After radical hysterectomy and lymphadenectomy, women with stage IB or IIA disease who have negative pelvic lymph nodes have a five-year survival of 88 to 96 percent, compared to 64 to 74 percent for those with similar stage disease and pelvic nodal metastasis . Outcomes are worse for women with involved paraaortic nodes . Among patients who have undergone surgical staging or lymphadenectomy, the number of involved lymph nodes also influences prognosis. As an example, in one report, five- year survival rates for patients with one, two, three to four, and five or more positive lymph nodes were 62, 36, 20 and 0 percent, respectively . The prognostic significance of pelvic lymph node micrometastases in women with early stage disease is unclear. The importance of LVI as an independent risk factor is controversial. A literature review reported that only three of 25 studies found that lymphovascular invasion was an independent risk factor affecting survival in patients with early cervical cancer and concluded the prognostic significance of LVI was questionable . HPV subtype The presence of persistent human papillomavirus (HPV) and specific HPV subtypes may also impact on prognosis after surgery or RT. In one population-based series of 399 women diagnosed with stage IB to IV cervical SCC over an 11 year period, 86 were HPV18-positive while 210 were HPV 16-positive . Compared to HPV 16, HPV 18 positivity was associated with a significantly higher overall and cause-specific mortality. This effect was most pronounced for FIGO stage IB and IIA tumors (hazard ratio [HR] 3.1). These findings were supported by another study that examined cancer-specific survival in 255 women with cervical cancer and HPV 18/45 . These women were significantly more likely to die of their disease than women with other HPV types or HPV16/31/52 (HRs 2.1 and 2.4, respectively). The prognosis was even worse in smokers. ( See "Cervical intraepithelial neoplasia: Etiology; diagnosis; and natural history").POSTTREATMENT FOLLOW-UP Surveillance after primary therapy for cervical cancer is uniformly recommended, although its effectiveness is not well studied . The main goal of surveillance is early detection of recurrent disease so that patients can be offered potentially curative salvage therapy. ( See "Management of recurrent or disseminated cervical cancer", section on Surgery and/or radiation therapy).Recommendations of expert groups The optimal surveillance strategy has not been established. Guidelines from the National Comprehensive Cancer Network (NCCN) suggest the following:
Clinical evaluation consists of a review of systems and physical examination with particular attention to the supraclavicular and inguinal lymph nodes, as well as rectovaginal and abdominal examinations. Cervical cytology is obtained at each visit, since many vaginal recurrences are asymptomatic, but have abnormal cytology smears . However, the value of cervical cytology in asymptomatic women has been questioned by others. Efficacy Few studies have specifically addressed the efficacy of routine surveillance for asymptomatic women compared to symptom-based reassessment. Retrospective series suggest that early detection of a localized disease recurrence in asymptomatic women may provide a survival benefit, but the best way to identify these women is unclear. One of these reports attempted to devise an optimal surveillance program based upon an outcomes analysis of 1096 women with stage 1B cervical cancer. A posttreatment surveillance strategy similar to that suggested by the NCCN was followed. Of the 133 women who recurred, only 19 were asymptomatic when diagnosed. All asymptomatic pelvic recurrences were diagnosed by pelvic examination, and routine cervical cytology smears did not detect a single case. The median survival from initial diagnosis was significantly longer among women diagnosed while asymptomatic (83 versus 31 months, respectively). The authors suggested that the follow-up strategy be modified to three annual clinical visits yearly for the first three years, twice yearly visits in years four and five, annual Pap tests, and an annual chest x-ray. Two other posttreatment surveillance tests have been studied: serial assay of the serum tumor marker squamous cell cancer tumor antigen (SCC antigen) and PET scanning. SCC antigen The value of serial assays of the serum tumor marker squamous cell carcinoma antigen (SCC antigen) has not been established. Elevated levels can precede clinical detection of recurrence by 4 to 16 months. However, in a review of 225 patients, SCC antigen was insensitive for the detection of early recurrence, and survival was no better among women whose disease recurrence was diagnosed by elevations in SCC antigen compared to those diagnosed by other means. PET scans Initial staging of cervical cancer is a Medicare-reimbursable indication for PET scanning. FDG-PET is a sensitive and specific method of detecting lymph node metastases in newly diagnosed cervical cancer, and most institutions perform a PET scan during initial staging as an adjunct to conventional imaging. The value of PET scanning following treatment for cervical cancer is unsettled. Results using PET or fused PET/CT for diagnosis of recurrent disease are variable. Several studies report sensitivity and specificity rates of 85 percent or higher in this setting . Others suggest limited sensitivity for lesions smaller than 1.5 cm , and lower specificity rates. Posttreatment FDG uptake is also reported to be a significant prognostic factor for outcomes after chemoradiotherapy. The value of PET as a component of routine posttreatment surveillance has not been systematically studied. The limitations of such an approach were noted in a report of 121 women who had undergone whole body PET at least six months after successfully completing treatment for primary cervical cancer; 76 were diagnosed with a recurrence, 20 of whom were asymptomatic at the time of diagnosis . PET scan was performed for a variety of reasons (tumor marker elevation, abnormal physical examination or imaging study, or abnormal histology on smear); 30 women received the test for no reason other than as a component of routine posttreatment surveillance. Although PET detected disease in 17 of 20 asymptomatic patients with recurrence (85 percent sensitivity), all had undergone the PET for workup of an abnormal finding. Six of the 30 patients who underwent a PET scan as a component of routine surveillance had a positive PET; all six were determined to be false positive studies. These data suggest that PET might be useful in the diagnostic workup of abnormal findings on physical examination or Pap smears, but they are insufficient to prove value from including PET in the routine posttreatment surveillance strategy. Summary In view of the lack of prospective data to guide posttreatment surveillance, it is not surprising that clinical practice varies. There is consensus on the need to perform clinical evaluation (a review of systems, physical examination with particular attention to the supraclavicular and inguinal lymph nodes as well as rectovaginal and abdominal examinations, cervical cytology) every three months for one year, every four months for one year, every six months for three years, and then annually, as per NCCN guidelines. The majority of clinicians also recommend an annual chest x-ray. There is a difference of opinion as to whether other radiographic studies are beneficial for early detection of an asymptomatic disease recurrence. Some clinicians (including one of the authors [JFD]) routinely perform CT of the abdomen and pelvis at three months after therapy, every six months for the first three years, then annually in year four and five. Others order radiographic studies only as clinically indicated by symptoms or findings on examination. HORMONE REPLACEMENT THERAPY As a result of cancer therapy, many women have reduced or absent ovarian hormone production, which causes hot flashes and vaginal dryness. There are scant data regarding use of hormone replacement therapy (HRT) after treatment of cervical cancer . Patients who have not undergone hysterectomy should have a discussion with their doctors regarding the risk to benefit ratio of HRT. If HRT is given, estrogen should be used in combination with progesterone, as residual functional endometrium may persist after curative RT for cervical cancer .SPECIAL CIRCUMSTANCES Special circumstances that need to be addressed in women with cervical cancer are:
Pregnancy The incidence of cervical cancer in pregnancy is approximately 1.2 per 10,000 pregnancies . Pregnancy does not appear to affect the prognosis in such women. The fetus is not affected by the maternal disease, but may suffer morbidity from its treatment (eg, preterm birth). The diagnosis and management of invasive cervix carcinoma during pregnancy poses challenges both for the patient and physician. Cervical punch biopsies can be safely performed without a significantly increased risk of excessive bleeding, but endocervical curettage should be avoided. In comparison, cone biopsy should be performed only if strictly indicated because of the increased risk of complications, such as hemorrhage, infection, pregnancy loss, and preterm labor. A combined procedure of conization and cerclage can be considered when cone biopsy is required. If the pregnancy is early and the disease is stage I or IIA, radical hysterectomy and therapeutic lymphadenectomy can be performed with the fetus left in-situ unless the patient is unwilling to terminate the pregnancy. Women at a gestational age closer to fetal viability or who are unwilling to lose the baby may decide to continue the pregnancy, after careful discussion regarding the maternal risks . Pregnant women with carcinoma in situ or microinvasive disease (up to 3 mm in depth, who had undergone full evaluation during pregnancy with a conization showing negative margins) may be followed to term and deliver vaginally, with reevaluation and treatment six weeks postpartum. Recurrences have been reported at the episiotomy site in women who deliver vaginally ; this area should be inspected and palpated during posttreatment surveillance. Delivery in women with larger volume, invasive cervical cancer should be by classical cesarean delivery to avoid potential cervical hemorrhage and possible dissemination of tumor cells during labor and vaginal birth, although the latter risk is controversial. A classical cesarean-radical hysterectomy with therapeutic lymphadenectomy is the treatment of choice for early lesions, after fetal pulmonary maturity is established. As in nonpregnant patients, advanced disease is generally treated with chemoradiotherapy, either with the previable fetus in situ or following delivery. With the fetus in situ, in most cases, miscarriage takes place and intracavitary RT can be added. In selected cases with locally advanced disease in which the patient declines pregnancy termination, consideration may be given to neoadjuvant chemotherapy in an effort to prevent disease progression during the time needed to achieve fetal viability. Incidentally diagnosed cancer Women found to have isolated microinvasive disease after a simple hysterectomy do not require any additional therapy. Patients with invasive disease who are good surgical candidates and who do not have gross parametrial disease can be treated by radical parametrectomy and upper vaginectomy with therapeutic lymphadenectomy. This approach may be particularly helpful in young women who desire ovarian preservation. The benefit of lymphadenectomy prior to chemoradiotherapy in patients with enlarged lymph nodes on posthysterectomy imaging studies is controversial RT is a suitable alternative to radical parametrectomy. It is the treatment of choice for women who are not candidates for radical pelvic surgery or those with more extensive disease that cannot be easily encompassed by a radical parametrectomy. Concomitant chemotherapy should be given according to the guidelines outlined above Carcinoma of the cervical stump Early stage cervical cancer noted on a cervical stump following a supracervical hysterectomy should be treated by radical trachelectomy with upper vaginectomy and therapeutic lymphadenectomy. Surgery is preferred over RT in this setting because the ability to deliver adequate doses of RT may be compromised in patients with a short cervical stump. In comparison, RT is generally preferred for patients with more advanced disease. SUMMARY AND RECOMMENDATIONS The treatment options for early stage (FIGO IA, IB1, nonbulky IIA, cervical cancer are as follows:
Randomized trials suggest that survival is similar with radical hysterectomy (including pelvic and paraaortic lymphadenectomy) with or without postoperative radiation therapy (RT) or definitive RT in women with FIGO stage IA, IB1, or nonbulky IIA cervical SCC.
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