Although detection and treatment of cervical cancer are improving, the disease continues to impose a significant burden of morbidity and mortality. Worldwide, cervical cancer remains the fourth leading cause of cancer death in women, and is especially common and onerous in the developing world where it is the second leading cause of cancer death.1 Advances in imaging, radiotherapy (RT), systemic therapy, and our understanding of disease biology offer new approaches to improve oncologic outcomes and reduce treatment-related toxicity. This document is based on a thorough literature review supplemented by expert opinion regarding the optimal practice in treating early-stage cervical cancer.
Cervical cancer staging has been recently updated by the International Federation of Gynecology and Obstetrics (FIGO).2 This staging system remains primarily clinical in nature and restricts the incorporation of information gleaned from modern imaging. It reflects the lack of medical resources in some areas and also helps to preserve the applicability of historical series to current practice. However, FIGO does endorse the use of computed tomography (CT), positron emission tomography (PET), and magnetic resonance imaging (MRI) and allows their findings to be used to guide therapy. An in-depth discussion of staging for cervical cancer can be found in the ACR Appropriateness Criteria® for “Pretreatment planning of invasive cancer of the cervix.”3
CT is an essential component for 3-dimensional conformal radiotherapy (3D-CRT) and intensity-modulated radiotherapy (IMRT) planning, and has some utility in assessing the extent of cervical cancer spread. CT outperforms chest radiographs in evaluating pulmonary metastasis and the presence of pleural effusions. CT has only modest sensitivity and specificity in identifying parametrial invasion due to difficulty in differentiating between tumor and normal parametrial structures.4 Similarly, the identification of involved lymph nodes is only moderately accurate with CT, likely owing to its reliance on a size-based criterion alone.5 MRI provides superior soft-tissue delineation compared with CT and, thus, yields a more precise assessment of tumor size and local extension, including parametrial invasion, than either CT or physical examination.4 MRI does not seem to exceed CT in accuracy of assessing cervical stromal invasion.6 PET, especially when used in combination with CT, seems to offer a notable improvement in the detection of involved lymph nodes and distant metastatic disease.7 However, a series evaluating the correlation between PET/CT identification of involved para-aortic lymph nodes and pathologic examination in women with stage IB or II disease found a false-negative rate of 8% for PET/CT.8 The false-negative rate of PET/CT for involved para-aortic lymph nodes seems to be even higher in locally advanced disease.9 Surgical staging may thus have a role in early-stage cervical cancer, leading to changes in the treatment plan by detecting radiographically occult nodal metastases, more accurately defining appropriate volumes for radiation therapy, and, possibly imparting a therapeutic advantage by clearing a reservoir of disease.10,11 Surgical clearance may be most appropriate in the treatment of bulky pelvic lymphadenopathy. Surgical staging may delay the start of RT due to wound healing, but the advent of laparoscopic nodal staging may allay this concern.
TREATMENT: SURGERY VERSUS RT
Cervical cancer stage IB1 or below can be appropriately treated with either surgery or definitive RT. Only a single randomized trial has compared surgery to RT in early-stage disease. Landoni et al12 randomized women with IB or IIA cervical cancer to surgery with or without postoperative RT versus definitive RT alone. Postoperative RT was administered to 64% of women in the surgery arm. The 2 treatment arms yielded identical overall survival (OS) and disease-free survival (DFS), although severe morbidity was higher in the surgery arm (28% vs. 12%), likely due to contributions from both treatment modalities. No trial has compared surgery to chemoradiotherapy. Both surgery and RT remain viable treatment options in early-stage disease and the choice may depend on institutional experience. Surgery, which allows for better preservation of ovarian and sexual function and eliminates the risk of radiation-induced malignancies, may be preferable in younger women. Definitive RT or chemoradiotherapy is preferred in patients likely to require postoperative RT to avoid compounding treatment-related morbidity.
Definitive RT for cervical cancer is typically delivered with external beam radiotherapy (EBRT) to the pelvis to approximately 45 to 50 Gy interdigitated with brachytherapy and lymph node boosts (if necessary). Although no randomized data evaluating the role of brachytherapy exist, it is considered to be an integral component of definitive RT, delivering high doses to the central tumor while preferentially sparing normal tissue.13,14 Retrospective data from Barillot et al15 and early patterns-of-care studies16 show local control in patients receiving brachytherapy to be far superior to that for patients receiving EBRT alone. In addition, the combination of EBRT and brachytherapy is associated with less toxicity as compared with EBRT alone.
EBRT has classically been delivered using 2-field or 4-field arrangements with field borders and blocks defined using bony landmarks to encompass the primary cervical disease, local extension, and regional lymph nodes. Incorporation of CT imaging allowed the use of 3D-CRT, in which contoured volumes could be used to define blocks or multileaf collimators and dose homogeneity could be fine tuned. More recently, IMRT has been used to reduce the volume of normal tissue receiving high-dose RT compared with supine 3D-CRT. Dosimetric analyses suggest that IMRT decreases the dose to small bowel, bladder, rectum, and bone marrow.17,18 Early clinical data also suggest that this improvement in dose distribution translates into a reduction in acute toxicity.19 However, multiple reports also show that tumor regression and normal tissue motion may lead to underdosing of target structures or overdosing of adjacent critical structures if not adequately considered in RT planning.20,21
Other positioning techniques or patient instructions have been considered to facilitate small bowel sparing. Specifically, the use of the prone position, pelvic compression, and belly board may displace small bowel out of the RT field.22 The presence of a full bladder may exert a similar effect on small bowel, although consistent daily bladder filling may be difficult to achieve and may be limited by the patient’s discomfort as the treatment progresses.23 An in-depth discussion of considerations in pelvic RT technique can be found in the ACR Appropriateness Criteria® for “Role of adjuvant therapy in the management of early stage cervical cancer.”24
Stereotactic body radiotherapy (SBRT) has been shown to be a useful treatment option in other tumor sites, especially in early-stage lung cancer. There are preliminary data on its use in treating cervical cancer,25 but, given target definition, tumor motion, and the proven track record of brachytherapy, SBRT should not be considered a substitute for brachytherapy26 (Table 1).
RT VERSUS CHEMORADIOTHERAPY
Historically, RT alone had been used to treat locally advanced or bulky cervical cancer. Several randomized trials have evaluated the utility of adding concurrent chemotherapy to that regimen; some of these trials included women with IB2 to IIA disease.27–30 Most showed an advantage in OS for the addition of concurrent chemotherapy, using a cisplatin-based regimen. In contrast, a National Cancer Institute—Canada (NCIC) trial randomized women to RT with or without concurrent weekly cisplatin chemotherapy and found no statistically significant advantage in progression-free survival (PFS) or OS.29 The notable discrepancy between the results of the NCIC trial and those of several others that support chemoradiotherapy may be explained by statistical variation, the presence of anemia in the chemoradiotherapy arm, or the absence of para-aortic lymph node surgical staging. Alternatively, chemotherapy may be compensating for the extended treatment time in most trials, whereas the NCIC trial achieved shorter average treatment duration. A Cochrane meta-analysis of all randomized trials comparing RT to chemoradiotherapy found a 6% survival advantage in favor of the latter.31 Moreover, there was a trend toward larger benefit for the addition of chemotherapy in stages IB to IIA as compared with more advanced stages. An advantage of chemoradiotherapy was present for both cisplatin-based and nonplatinum-based chemotherapy regimens. Likely due to an NCI alert issued in 1999 recommending concurrent cisplatin-based chemoradiotherapy, weekly cisplatin is by far the most commonly used agent.32 Caution is advised with the use of chemotherapy doublets containing cisplatin and fluorouracil (5-FU), gemcitabine, or taxol; each of these regimens is more toxic than cisplatin alone, especially when used concurrently with extended-field radiotherapy (EFRT). No randomized data exist concerning the use of chemoradiotherapy in stage IB1 or below.
INDUCTION CHEMOTHERAPY FOLLOWED BY SURGERY
In countries with limited RT resources, bulky cervical cancer is often treated with induction chemotherapy followed by hysterectomy. Three randomized trials included women with bulky stage IB, who were disease randomized to chemotherapy followed by surgery versus RT alone.33–35 These trials yielded mixed results, with some suggesting an advantage for induction chemotherapy and surgery over definitive RT and one showing equivalency. A meta-analysis that included these trials and trials of women with higher stage disease also supported the superiority of chemotherapy followed by surgery over RT.36 However, the validity and applicability of these studies have been challenged. The RT in these trials was of poor quality due to inadequate dose, protracted delivery schedules, and the absence of concurrent chemotherapy. Interestingly, a meta-analysis of induction chemotherapy followed by surgery versus surgery alone failed to show a clear benefit for the induction chemotherapy arms.37 For these reasons, the appropriateness of induction chemotherapy followed by surgery remains uncertain, and it should be performed only in the context of a clinical trial. The issue most relevant to modern therapy is whether concurrent chemoradiotherapy or induction chemotherapy followed by hysterectomy is preferred. This issue is currently being evaluated in 2 phase III clinical trials: EORTC 55994 and NCT 00193739. In the interim, consensus supports the use of chemoradiotherapy as the preferred treatment modality for tumors above stage IB138 (Table 2).
The role of EFRT to the para-aortic lymph node chain with definitive RT alone was supported by the Radiation Therapy Oncology Group® (RTOG®) 79-20.39 Women with bulky IB/IIA (≥5 cm or with positive pelvic nodes) or IIB tumors were randomized to receive pelvic RT alone or EFRT. Although no differences in locoregional recurrence or DFS were evident, a benefit in 10-year OS emerged. This difference seems to be due to a reduction in the rate of distant metastatic disease and an improvement in the rate of salvage after local recurrence. This prompted the comparison between pelvic RT administered concurrently with chemotherapy versus EFRT alone in RTOG® 90-01.27 The mature analysis of this trial showed a large benefit in both DFS and OS for the pelvic RT plus chemotherapy arm. Interestingly, there was an improvement as well in the risk of distant metastasis in the pelvic RT with concurrent cisplatin and 5-FU chemotherapy. The role of prophylactic EFRT in addition to concurrent chemotherapy is unclear given the significant acute and late toxicity associated with combination treatment.40,41 RTOG® 0116, a multi-institutional study evaluating the toxicity of EFRT with concurrent cisplatin, found an acute grade 3/4 toxicity rate excluding grade 3 leukopenia of 81% and a late grade 3/4 toxicity of 40%.
Patient-specific risk factors for toxicity such as obesity, diabetes mellitus, and smoking may be important considerations when selecting the appropriate RT fields. More conformal means of delivering RT, such as IMRT, may have a role in reducing toxicity.18 In addition, the advent of PET, which can identify some nodal metastases occult to CT imaging, may reduce the benefit of prophylactic RT to an uninvolved nodal chain.
When not using EFRT, the superior border of pelvic RT fields has traditionally been the L4/L5 interspace. This bony landmark was thought to correlate to the top of the common iliac chain. The use of 3D-CRT has shown that the bifurcation of the aorta is frequently superior to L4/L5. Ideally, the pelvic field should be designed with 3D-CRT so as to include the common iliac vessels. If 3D-CRT is unavailable, then the L3/L4 interspace may be a preferred field border. This is supported by an analysis of regional recurrences after definitive RT for cervical cancer from the M.D. Anderson Cancer Center, which suggested that most regional recurrences occurred immediately superior to the pelvic field border at approximately L4/L5.42
A single randomized trial evaluated the incremental benefit of extrafascial hysterectomy after definitive RT. In GOG 71, women with bulky IB cervical cancer were randomized to receive RT alone to 80 Gy or RT to 75 Gy followed by hysterectomy.43 Although there was a trend toward better local control in the hysterectomy group, there was no benefit in OS. This trial has been criticized for the relatively low dose used in the RT-alone arm, the protracted RT schedule, and the absence of concurrent chemotherapy. The subsequent GOG study, GOG 123,28,44 confirmed the benefit of concurrent chemoradiotherapy in this patient population. As GOG 71 did not demonstrate a survival benefit for the addition of “adjuvant” extrafascial hysterectomy, the authors indicated that “It is reasonable to conclude on the basis of these results and our results that the elimination of hysterectomy from both regimens would not have affected the increase in survival associated with the use of cisplatin. Therefore, RT in combination with treatment with cisplatin should be adequate for patients with bulky stage IB cervical cancer.”
Given the dearth of randomized data, there are no clear guidelines as to when, or in whom, RT or chemoradiotherapy should be followed by extrafascial hysterectomy. It should probably be limited to patients with bulky residual disease at the time of the brachytherapy (generally after 45 Gy EBRT+chemotherapy), to patients whose anatomy prevents an adequate implant, and perhaps to some patients with adenocarcinomas, although level 1 evidence is lacking. Some investigators have evaluated the role of posttreatment biopsy, MRI, or PET to identify patients with residual disease, who may benefit from surgery while sparing most patients the added morbidity.45–47 This remains an area of active investigation.
Pelvic control rates have improved with modern therapeutic techniques, leaving development of distant metastatic disease an ever more important competing risk. This is especially true in lymph node-positive disease. In addition, conflicting evidence points to a possibly higher likelihood of distant metastases for nonsquamous (notably adenocarcinoma and adenosquamous) histologies, suggesting a role for systemic therapy.48,49 Even in higher risk subsets of early-stage cervical carcinoma, the utility of adjuvant chemotherapy remains unclear. A randomized trial investigating the role of intensification of the chemotherapeutic regimen in locoregionally advanced cervical cancer compared concurrent single-agent cisplatin versus concurrent and adjuvant cisplatin and gemcitabine.50 This trial found an OS advantage for the cisplatin plus gemcitabine arm (hazard ratio=0.68) at the cost of a significant increase in toxicity; grade 3/4 toxicity rates were 86.5% in the experimental arm versus 46.3% in the cisplatin-alone arm. It remains to be seen whether these findings can be replicated in early-stage disease, and whether the benefit is attributable to the addition of gemcitabine or to additional cycles of cisplatin. Due in part to benefits of extended adjuvant chemotherapy in the SWOG trial, the Chemoradiotherapy for Cervical Cancer Meta-analysis Collaboration supports this as a promising area of research.31 The utility of adjuvant chemotherapy after chemoradiotherapy in the setting of high-risk postoperative cervical cancer is currently under study by the RTOG® (Phase III randomized study of concurrent chemotherapy and pelvic radiation therapy with or without adjuvant chemotherapy in high-risk patients with early-stage cervical carcinoma following radical hysterectomy; http://www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.aspx?study=0724). Until more data are collected, adjuvant chemotherapy may be most appropriately used in the setting of a clinical trial.
HEMOGLOBIN (Hgb) LEVEL
A clear association is seen between Hgb level and prognosis in cervical cancer treated with RT or chemoradiotherapy.51 Whether anemia has a causative relationship with disease recurrence—possibly through hypoxic radioprotection or induction of a more malignant phenotype—or whether anemia represents an epiphenomenon associated with, but not responsible for, poor prognosis is unclear. A multi-institutional retrospective analysis suggests that average weekly nadir of Hgb (AWNH) is highly predictive for outcome.52 In this study, transfusion compensated for the negative prognostic effects of anemia, rendering women who received transfusions with prognoses similar to those with comparable baseline AWNH levels. Transfusion may be especially important in women with lower tumor perfusion on MRI.53 However, to this date, no randomized data support therapeutic transfusion, and the minimum acceptable Hgb is unclear. The role of erythropoietin to raise Hgb levels seems to be limited after a phase III trial closed prematurely due to concerns about elevated risk of thromboembolic events.54 Although analysis was quite limited due to low accrual before study closure, there was no suggestion of benefit with regard to PFS or OS in the experimental arm. In fact a nonstatistically significant detrimental effect was noted in the PFS (58% vs. 65% at 3 y) and OS (61% vs. 75% at 3 y) in the arm receiving erythropoietin compared with the standard arm.54
Brachytherapy is an integral component of the definitive treatment of cervical cancer using RT or chemoradiotherapy. Intracavitary brachytherapy, typically performed using a tandem and ovoids or a tandem and ring, is the most standard approach. Classically, 2-dimensional dosimetry is performed using the Manchester nomenclature or comparable formalism. More recently, the GEC-ESTRO created guidelines recommending 3D dosimetry incorporating delineation of the target volume and organs at risk to improve target coverage and normal tissue sparing.55 MRI simulation or fusion of MRI images with CT simulation may be beneficial to identify the extent of tumor spread. Early experience with MRI planning has yielded favorable outcomes.56 In circumstances where insertion of an intracavitary brachytherapy is not feasible or is inadequate to cover the central tumor volume (eg, vaginal extension, anatomic distortion due to tumor, or bulky disease), the use of interstitial brachytherapy may be advantageous. Consideration should be given to performing interstitial brachytherapy under laparoscopic guidance to perform lysis of adhesions, identify possible carcinomatosis, and avoid visceral puncture. However, some reports suggest that laparoscopy does not reduce toxicity.57,58 Brachytherapy can be performed using low-dose rate, high-dose rate, or pulsed-dose rate delivery of RT. A recent meta-analysis of available randomized trials supports the equivalency of low-dose rate and high-dose rate with regard to local control, OS, and late complications to the rectum or bladder.59 Every effort should be made to perform treatment planning for each brachytherapy insertion and to carefully balance the doses needed for tumor control with those recommended to minimize normal tissue toxicity60 (Table 3).
OVERALL TREATMENT TIME
Several retrospective series consistently show an association between prolongation of overall treatment time of RT and a reduction in local control and survival.61,62 The nonrandomized nature of these studies prohibits concluding a causative relationship with certainty, but these findings are likely the result of accelerated repopulation of tumor clonogens during treatment breaks. These results have not been verified in a randomized trial, in part due to an absence of equipoise, and most reports predate the widespread use of chemoradiotherapy. However, overall treatment time seems to be one of the most powerful predictors of the outcome and should be a key driver in the design of the treatment paradigm. Unfortunately, survey data suggest this goal is often not met in clinical practice.13
An in-depth discussion of the role of postoperative RT or chemoradiotherapy can be found in the ACR Appropriateness Criteria® for “Role of adjuvant therapy in the management of early stage cervical cancer.”24
The majority of the panel supported performing cervical cytology and physical examination every 3 to 6 months for the first 5 years and then annually. Chest radiograph is considered reasonable. Although its role is under investigation, a PET/CT at 3 months to evaluate the extent of residual disease is favored.46
Treatment for persistent or recurrent disease after definitive RT or chemoradiotherapy is challenging. Workup should include biopsy to prove the nature of the recurrence and staging examinations to rule out metastatic disease. If feasible, surgery presents the best option for cure; the type of surgery—radical hysterectomy versus exenteration—should be dictated by the extent of disease. Interstitial brachytherapy may be indicated, especially if the first course of RT was compromised due to prolongation of treatment course, marginal miss of tumor, inadequacy of dose, or suboptimal brachytherapy technique. Other options include systemic therapy such as chemotherapy and use of emerging biological agents.
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