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  • Guideline Summary
  • NGC:009216
  • 2012

ACR Appropriateness Criteria® definitive therapy for early stage cervical cancer.

Small W Jr, Strauss JB, Jhingran A, Yashar CM, Gaffney DK, Cardenes HR, Erickson-Wittmann BA, Gullett N, Kidd E, Lee L, Mayr NA, Moore D, Puthawala AA, Rao GG, Varia MA, Wahl AO, Wolfson AH, Yuh W, Expert Panel on Radiation Oncology–Gynecology. ACR Appropriateness Criteria® definitive therapy for early stage cervical cancer. [online publication]. Reston (VA): American College of Radiology (ACR); 2012. 10 p. [61 references]

View the original guideline documentation External Web Site Policy

This is the current release of the guideline.

Age Group

UMLS Concepts (what is this?)

Major Recommendations

ACR Appropriateness Criteria®

Clinical Condition: Definitive Therapy for Early Stage Cervical Cancer

Variant 1: 50-year-old woman with FIGO clinical stage IB1 poorly differentiated squamous cell carcinoma of the cervix. No evidence of lymph node metastasis on imaging.

Treatment Rating Comments
Treatment

Surgery

8  

Radiotherapy

8  

Chemoradiotherapy

6  
Radiotherapy Technique

3D-CRT

9  

2D radiotherapy

5 May be appropriate in resource-poor settings.

IMRT

5  
Brachytherapy

EBRT and brachytherapy

9  

EBRT alone

2  

EBRT and SBRT

2  
Overall Treatment Time

<56 days

9  

56-70 days

5  

>70 days

1  
Rating Scale: 1,2,3 Usually not appropriate; 4,5,6 May be appropriate; 7,8,9 Usually appropriate

Note: Abbreviations used in the tables are listed at the end of the "Major Recommendations" field.

Variant 2: 45-year-old woman with FIGO clinical stage IB2, 6 cm diameter, moderately differentiated adenocarcinoma, PET negative for nodal or distant metastatic disease. Hemoglobin (Hgb) at presentation 7 g/dl.

Treatment Rating Comments
Treatment of Cervical Primary

Chemoradiotherapy to 85-90 Gy

9  

Chemoradiotherapy to 75 Gy followed by extrafascial hysterectomy

5  

Radiotherapy alone

3  

Induction chemotherapy followed by surgery

2  
Upper Field Border if Using RT Alone (LN -)

Bifurcation of aorta

8  

Bony landmark of L4/L5

7  

Mid para-aortic chain (~L1/L2)

4  

Extended field RT to T11/T12

2  
Upper Border of Field if Using Chemoradiotherapy (LN -)

Bifurcation of aorta

8  

Bony landmark of L4/L5

7  

Bony landmark of L5/S1

3  

Mid para-aortic chain (~L1/L2)

2  
Hemoglobin

Transfuse to maintain Hgb 10-11.9 during RT

8  

Transfuse to maintain Hgb ≥12 during RT

4  

Do not transfuse during RT

2  

Administer erythropoietin during RT

1  
Rating Scale: 1,2,3 Usually not appropriate; 4,5,6 May be appropriate; 7,8,9 Usually appropriate

Note: Abbreviations used in the tables are listed at the end of the "Major Recommendations" field.

Variant 3: 30-year-old woman with FIGO clinical stage IIA, 5 cm diameter, poorly differentiated adenosquamous carcinoma with uterine extension, PET positive left external iliac-obturator node without evidence of distant metastatic disease.

Treatment Rating Comments
Treatment of Primary

Chemoradiotherapy

9  

Chemoradiotherapy followed by additional chemotherapy

5  

Neoadjuvant chemotherapy followed by local treatment

2  

Radiation therapy alone

2  
Node Dissection Prior to Start of Radiation Therapy

No node dissection

7  

Para-aortic node dissection

6  

Pelvic and para-aortic node dissection

5  
Radiotherapy Boost to Undissected Pelvic Node (include brachytherapy contribution)

Boost involved node to 60-65 Gy

9  

No boost

3  
Top of the Radiation Field in a Patient with PET Positive Pelvic Node and Negative Common/Para-aortic Nodes with no Node Dissection

Bifurcation of aorta

8  

L3/L4

7  

L4/L5

5  

L2/L3

5  

L1/L2

5  
Type of Chemotherapy

Concurrent chemotherapy

9  

Concurrent chemotherapy followed by additional chemotherapy

5  

Neoadjuvant chemotherapy followed by concurrent chemoradiotherapy

2  
If Treating Higher than L4/L5

Concurrent chemotherapy

8  

No chemotherapy

2  
Type of Concurrent Chemotherapy

Weekly cisplatin

9  

Cisplatin and 5-FU

5  

Cisplatin and gemcitabine

3  

Weekly taxol

3  

Cisplatin and taxol

3  
Type of Intracavitary Brachytherapy

LDR

9  

HDR

9  

PDR

9  
Rating Scale: 1,2,3 Usually not appropriate; 4,5,6 May be appropriate; 7,8,9 Usually appropriate

Note: Abbreviations used in the tables are listed at the end of the "Major Recommendations" field.

Variant 4: 55-year-old woman status postsupracervical hysterectomy 20 years earlier, now with a FIGO clinical stage IB2, 5 cm diameter, well-differentiated squamous cell carcinoma, PET negative for nodal regional or distant metastatic disease. Tandem cannot be placed in the residual cervix.

Treatment Rating Comments
Treatment of Primary

Chemoradiotherapy

9  

Surgery followed by RT or chemoradiotherapy

5  

Surgery

3  

Radiation therapy alone

2  
If Conformal Radiotherapy Selected

EBRT and brachytherapy

9  

Prone with belly board

8  

Supine

8  

Bladder full for simulation and daily treatment

8  

EBRT alone (including IMRT)

4  

EBRT and SBRT

2  
Interstitial Brachytherapy

CT for treatment planning

9  

MRI for treatment planning before implant

8  

Laparoscopic guidance

8  
Rating Scale: 1,2,3 Usually not appropriate; 4,5,6 May be appropriate; 7,8,9 Usually appropriate

Note: Abbreviations used in the tables are listed at the end of the "Major Recommendations" field.

Summary of Literature Review

Introduction

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. 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.

Staging

Cervical cancer staging has been recently updated by the International Federation of Gynecology and Obstetrics (FIGO). 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 National Guideline Clearinghouse (NGC) summary of the ACR Appropriateness Criteria® pretreatment planning of invasive cancer of the cervix.

CT is an essential component for 3-dimensional conformal RT (3D-CRT) and intensity-modulated RT (IMRT) planning and has some utility in assessing the extent of cervical cancer spread. CT outperforms chest radiograph 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. Similarly, the identification of involved lymph nodes is only moderately accurate with CT, likely owing to its reliance on a size-based criterion alone. MRI provides superior soft-tissue delineation compared to CT and thus yields more a precise assessment of tumor size and local extension, including parametrial invasion, than either CT or physical examination. MRI does not appear to exceed CT in accuracy of assessing cervical stromal invasion. PET, especially when used in combination with CT, appears to offer a notable improvement in the detection of involved lymph nodes and distant metastatic disease. 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. The false-negative rate of PET/CT for involved para-aortic lymph nodes appears to be even higher in locally advanced disease. 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. 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 Radiotherapy

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. In the trial, women with IB or IIA cervical cancer were randomized to surgery with or without postoperative RT versus definitive RT alone. Postoperative RT was administered to 64% of women in the surgery arm. The two 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 in order to avoid compounding treatment-related morbidity.

Radiotherapy Technique

Definitive RT for cervical cancer is typically delivered with external beam RT (EBRT) to the pelvis to approximately 45-50 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. Retrospective data from one study as well as early patterns-of-care studies show local control in patients receiving brachytherapy to be far superior to that for patients receiving EBRT alone. Additionally, the combination of EBRT and brachytherapy is associated with less toxicity as compared to EBRT alone.

EBRT has classically been delivered using 2-field or 4-field arrangements with field borders and blocks defined using bony landmarks in order 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 (MLCs) 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 to supine 3D-CRT. Dosimetric analyses suggest that IMRT decreases the dose to small bowel, bladder, rectum, and bone marrow. Early clinical data also suggest that this improvement in dose distribution translates into a reduction in acute toxicity. 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.

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. 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. An in-depth discussion of considerations in pelvic radiotherapy technique can be found in the NGC summary ACR Appropriateness Criteria® role of adjuvant therapy in the management of early stage cervical cancer.

Stereotactic body RT (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, but, given target definition, tumor motion, and the proven track record of brachytherapy, SBRT should not be considered a substitute for brachytherapy. (See Variant 1 above.)

Radiotherapy 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-IIA disease. Most showed an advantage in OS for the addition of concurrent chemotherapy, using a cisplatin-based regimen. By 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. 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. Moreover, there was a trend towards larger benefit for the addition of chemotherapy in stages IB-IIA as compared to 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. Caution is advised with the use of chemotherapy doublets containing cisplatin as well as fluorouracil (5-FU), gemcitabine, or taxol; each of these regimens is more toxic than cisplatin alone, especially when used concurrently with extended-field RT (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. 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. 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. 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 two 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 IB1. (See Variant 2 above.)

Extended-Field Radiotherapy (EFRT)

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. Women with bulky IB/IIA (greater or equal to 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 appears 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. 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. 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. Additionally, 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.

Adjuvant Hysterectomy

A single randomized trial evaluated the incremental benefit of extrafascial hysterectomy after definitive RT. In Gynecologic Oncology Group (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. Although there was a trend towards 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, confirmed the benefit of concurrent chemoradiotherapy in this patient population. Since 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 one evidence is lacking. Some investigators have evaluated the role of post-treatment biopsy, MRI, or PET to identify patients with residual disease who may benefit from surgery while sparing most patients the added morbidity. This remains an area of active investigation.

Adjuvant Chemotherapy

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. Also, conflicting evidence points to a possibly higher likelihood of distant metastases for nonsquamous (notably adenocarcinoma and adenosquamous) histologies, suggesting a role for systemic therapy. 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. 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 Southwest Oncology Group (SWOG) trial, the Chemoradiotherapy for Cervical Cancer Meta-analysis Collaboration supports this as a promising area of research. 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. Available at: http://www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.aspx?study=0724 External Web Site Policy.) Until more data are collected, adjuvant chemotherapy may be most appropriately used in the setting of a clinical trial.

Hemoglobin Level

A clear association is seen between hemoglobin (Hgb) level and prognosis in cervical cancer treated with RT or chemoradiotherapy. 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 hemoglobin (AWNH) is highly predictive for outcome. 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. 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 appears to be limited after a phase III trial closed prematurely due to concerns about elevated risk of thromboembolic events. Although analysis was quite limited due to low accrual prior to 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 years) and OS (61% vs 75% at 3 years) in the arm receiving erythropoietin compared with the standard arm.

Brachytherapy

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, two-dimensional dosimetry is performed using the Manchester nomenclature or comparable formalism. More recently, the Groupe Européen de Curiethérapie and the European Society for Therapeutic Radiology and Oncology (GEC-ESTRO) created guidelines recommending 3D dosimetry incorporating delineation of the target volume and organs at risk in order to improve target coverage and normal tissue sparing. 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. In circumstances where insertion of an intracavitary brachytherapy is not feasible or is inadequate to cover the central tumor volume (e.g., 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. Brachytherapy can be performed using low-dose-rate (LDR), high-dose-rate (HDR), or pulsed-dose-rate (PDR) delivery of RT. A recent meta-analysis of available randomized trials supports the equivalency of LDR and HDR with regard to local control, OS, and late complications to the rectum or bladder. 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 toxicity. (See Variant 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. 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 appears to be one of the most powerful predictors of 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.

Postoperative Radiotherapy

An in-depth discussion of the role of postoperative RT or chemoradiotherapy can be found in the NGC summary ACR Appropriateness Criteria® role of adjuvant therapy in the management of early stage cervical cancer.

Cervical Cancer after Supracervical Hysterectomy

The scenario of a cervical cancer presenting in the cervical stump after prior supracervical hysterectomy comprises approximately 5% of newly diagnosed cases. Therapy is complicated by the frequent inability to place a tandem, the displacement of small bowel into the low pelvis, and the likely presence of adhesions tethering organs at risk to radiation aimed at target tissue. If surgery is not feasible, definitive RT or chemoradiotherapy is indicated. In circumstances where intracavitary brachytherapy is not feasible, interstitial brachytherapy by experienced users should be considered. Referral to an experienced center may be preferred, since EBRT without brachytherapy is less likely to achieve durably tumor control. In circumstances where brachytherapy is not feasible, treatment with EBRT alone – including IMRT – is appropriate. SBRT should be reserved for use on a clinical trial, given the limited clinical data and concerns about organ motion. The use of MRI to guide treatment planning, obtained prior to implant or after needle insertion (with MRI-compatible template) is strongly encouraged. Only a few retrospective series describe outcomes after RT in this setting, and none routinely used concurrent chemotherapy. Treatment of cancer of the cervical stump may be associated with increased toxicity due to anatomic shifts after hysterectomy; the use of 3D-CRT or IMRT may ameliorate this risk to some degree, although care should be taken to account for intrafraction motion and setup uncertainty. Prone position and full bladder instructions should also be considered. Outcomes vary by stage, but 5-year OS ranges from 82% to 91% for stage I, 73% to 78% for stage II, 38% to 69% for stage III, and 0% to 37% for stage IV. (See Variant 4 above.)

Follow-up

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.

Salvage Therapy

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 biologic agents.

Abbreviations

  • 2D, 2-dimensional
  • 3D-CRT, 3-dimensional conformal radiotherapy
  • 5-FU, fluorouracil
  • CT, computed tomography
  • FIGO, International Federation of Gynecology and Obstetrics
  • EBRT, external beam radiotherapy
  • HDR, high-dose-rate
  • IMRT, intensity-modulated radiotherapy
  • LDR, low-dose-rate
  • LN, lymph node
  • MRI, magnetic resonance imaging
  • PDR, pulsed-dose-rate
  • PET, positron emission tomography
  • RT, radiotherapy
  • SBRT, stereotactic body radiotherapy

Clinical Algorithm(s)

Algorithms were not developed from criteria guidelines.

Disease/Condition(s)

Early stage cervical cancer

Guideline Category

Risk Assessment

Treatment

Clinical Specialty

Family Practice

Internal Medicine

Obstetrics and Gynecology

Oncology

Radiation Oncology

Radiology

Surgery

Intended Users

Health Plans

Hospitals

Managed Care Organizations

Physicians

Utilization Management

Guideline Objective(s)

To evaluate the appropriateness of treatment procedures for patients with early stage cervical cancer

Target Population

Patients with early stage cervical cancer

Interventions and Practices Considered

  1. Surgery
  2. Radiotherapy (RT)
    • 3-dimensional conformal RT (3D-CRT)
    • 2-dimensional (2D) RT
    • Intensity-modulated RT (IMRT)
    • Boost RT
    • External beam RT (EBRT)
    • Stereotactic body RT (SBRT)
  3. Chemoradiotherapy
    • Followed by extrafascial hysterectomy
    • Neoadjuvant, followed by local treatment
    • Concurrent, such as cisplatin, gemcitabine, and 5-fluorouracil
  4. Induction chemotherapy, followed by surgery
  5. Brachytherapy
    • Intracavity, including low-dose rate (LDR), high-dose rate (HDR), and pulsed-dose rate (PDR)
    • Interstitial, including computed tomography (CT) or magnetic resonance imaging (MRI) for treatment planning
  6. Hemoglobin
  7. Node dissection prior to RT
    • Para-aortic
    • Pelvic and para-aortic
  8. Treatment time

Major Outcomes Considered

  • Overall and disease-free survival
  • Local control
  • Locoregional recurrence
  • Risk of distant metastasis
  • Treatment-associated toxicity

Methods Used to Collect/Select the Evidence

Searches of Electronic Databases

Description of Methods Used to Collect/Select the Evidence

Literature Search Procedure

The Medline literature search is based on keywords provided by the topic author. The two general classes of keywords are those related to the condition (e.g., ankle pain, fever) and those that describe the diagnostic or therapeutic intervention of interest (e.g., mammography, MRI).

The search terms and parameters are manipulated to produce the most relevant, current evidence to address the American College of Radiology Appropriateness Criteria (ACR AC) topic being reviewed or developed. Combining the clinical conditions and diagnostic modalities or therapeutic procedures narrows the search to be relevant to the topic. Exploding the term "diagnostic imaging" captures relevant results for diagnostic topics.

The following criteria/limits are used in the searches.

  1. Articles that have abstracts available and are concerned with humans.
  2. Restrict the search to the year prior to the last topic update or in some cases the author of the topic may specify which year range to use in the search. For new topics, the year range is restricted to the last 5 years unless the topic author provides other instructions.
  3. May restrict the search to Adults only or Pediatrics only.
  4. Articles consisting of only summaries or case reports are often excluded from final results.

The search strategy may be revised to improve the output as needed.

Number of Source Documents

The total number of source documents identified as the result of the literature search is not known.

Methods Used to Assess the Quality and Strength of the Evidence

Weighting According to a Rating Scheme (Scheme Given)

Rating Scheme for the Strength of the Evidence

Strength of Evidence Key

Category 1 - The conclusions of the study are valid and strongly supported by study design, analysis and results.

Category 2 - The conclusions of the study are likely valid, but study design does not permit certainty.

Category 3 - The conclusions of the study may be valid but the evidence supporting the conclusions is inconclusive or equivocal.

Category 4 - The conclusions of the study may not be valid because the evidence may not be reliable given the study design or analysis.

Methods Used to Analyze the Evidence

Review of Published Meta-Analyses

Systematic Review with Evidence Tables

Description of the Methods Used to Analyze the Evidence

The topic author drafts or revises the narrative text summarizing the evidence found in the literature. American College of Radiology (ACR) staff draft an evidence table based on the analysis of the selected literature. These tables rate the strength of the evidence for all articles included in the narrative text.

The expert panel reviews the narrative text, evidence table, and the supporting literature for each of the topic-variant combinations and assigns an appropriateness rating for each procedure listed in the table. Each individual panel member forms his/her own opinion based on his/her interpretation of the available evidence.

More information about the evidence table development process can be found in the ACR Appropriateness Criteria® Evidence Table Development document (see the "Availability of Companion Documents" field).

Methods Used to Formulate the Recommendations

Expert Consensus (Delphi)

Description of Methods Used to Formulate the Recommendations

Modified Delphi Technique

The appropriateness ratings for each of the procedures included in the Appropriateness Criteria topics are determined using a modified Delphi methodology. A series of surveys are conducted to elicit each panelist's expert interpretation of the evidence, based on the available data, regarding the appropriateness of an imaging or therapeutic procedure for a specific clinical scenario. American College of Radiology (ACR) staff distributes surveys to the panelists along with the evidence table and narrative. Each panelist interprets the available evidence and rates each procedure. The surveys are completed by panelists without consulting other panelists. The ratings are a scale between 1 and 9, which is further divided into three categories: 1, 2, or 3 is defined as "usually not appropriate"; 4, 5, or 6 is defined as "may be appropriate"; and 7, 8, or 9 is defined as "usually appropriate." Each panel member assigns one rating for each procedure per survey round. The surveys are collected and the results are tabulated, de-identified and redistributed after each round. A maximum of three rounds are conducted. The modified Delphi technique enables each panelist to express individual interpretations of the evidence and his or her expert opinion without excessive bias from fellow panelists in a simple, standardized and economical process.

Consensus among the panel members must be achieved to determine the final rating for each procedure. Consensus is defined as eighty percent (80%) agreement within a rating category. The final rating is determined by the median of all the ratings once consensus has been reached. Up to three rating rounds are conducted to achieve consensus.

If consensus is not reached, the panel is convened by conference call. The strengths and weaknesses of each imaging procedure that has not reached consensus are discussed and a final rating is proposed. If the panelists on the call agree, the rating is accepted as the panel's consensus. The document is circulated to all the panelists to make the final determination. If consensus cannot be reached on the call or when the document is circulated, "No consensus" appears in the rating column and the reasons for this decision are added to the comment sections.

Rating Scheme for the Strength of the Recommendations

Not applicable

Cost Analysis

A formal cost analysis was not performed and published cost analyses were not reviewed.

Method of Guideline Validation

Internal Peer Review

Description of Method of Guideline Validation

Criteria developed by the Expert Panels are reviewed by the American College of Radiology (ACR) Committee on Appropriateness Criteria.

Type of Evidence Supporting the Recommendations

The recommendations are based on analysis of the current literature and expert panel consensus.

Potential Benefits

Selection of appropriate treatment procedures for early stage cervical cancer

Potential Harms

  • A series evaluating the correlation between positron emission tomography/computed tomography (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.
  • The combination of external beam radiotherapy (EBRT) and brachytherapy is associated with less toxicity as compared to EBRT alone.
  • The role of prophylactic extended-field radiotherapy (EFRT) in addition to concurrent chemotherapy is unclear given the significant acute and late toxicity associated with combination treatment. Radiation Therapy Oncology Group (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%.
  • Caution is advised with the use of chemotherapy doublets containing cisplatin as well as fluorouracil (5-FU), gemcitabine, or taxol; each of these regimens is more toxic than cisplatin alone, especially when used concurrently with EFRT.
  • Treatment of cancer of the cervical stump may be associated with increased toxicity due to anatomic shifts after hysterectomy.

Qualifying Statements

The American College of Radiology (ACR) Committee on Appropriateness Criteria and its expert panels have developed criteria for determining appropriate imaging examinations for diagnosis and treatment of specified medical condition(s). These criteria are intended to guide radiologists, radiation oncologists, and referring physicians in making decisions regarding radiologic imaging and treatment. Generally, the complexity and severity of a patient's clinical condition should dictate the selection of appropriate imaging procedures or treatments. Only those examinations generally used for evaluation of the patient's condition are ranked. Other imaging studies necessary to evaluate other co-existent diseases or other medical consequences of this condition are not considered in this document. The availability of equipment or personnel may influence the selection of appropriate imaging procedures or treatments. Imaging techniques classified as investigational by the U.S. Food and Drug Administration (FDA) have not been considered in developing these criteria; however, study of new equipment and applications should be encouraged. The ultimate decision regarding the appropriateness of any specific radiologic examination or treatment must be made by the referring physician and radiologist in light of all the circumstances presented in an individual examination.

Description of Implementation Strategy

An implementation strategy was not provided.

IOM Care Need

Getting Better

Living with Illness

IOM Domain

Effectiveness

Bibliographic Source(s)

Small W Jr, Strauss JB, Jhingran A, Yashar CM, Gaffney DK, Cardenes HR, Erickson-Wittmann BA, Gullett N, Kidd E, Lee L, Mayr NA, Moore D, Puthawala AA, Rao GG, Varia MA, Wahl AO, Wolfson AH, Yuh W, Expert Panel on Radiation Oncology–Gynecology. ACR Appropriateness Criteria® definitive therapy for early stage cervical cancer. [online publication]. Reston (VA): American College of Radiology (ACR); 2012. 10 p. [61 references]

Adaptation

Not applicable: The guideline was not adapted from another source.

Date Released

2012

Guideline Developer(s)

American College of Radiology - Medical Specialty Society

Source(s) of Funding

The American College of Radiology (ACR) provided the funding and the resources for these ACR Appropriateness Criteria®.

Guideline Committee

Committee on Appropriateness Criteria, Expert Panel on Radiation Oncology-Gynecology

Composition of Group That Authored the Guideline

Panel Members: William Small Jr, MD (Principal Author); Jonathan B. Strauss, MD, MBA (Research Author); Anuja Jhingran, MD (Co-Author); Catheryn M. Yashar, MD (Co-Author); David K. Gaffney, MD, PhD (Panel Chair); Higinia Rosa Cardenes, MD, PhD (Panel Vice-chair); Beth A. Erickson-Wittmann, MD; Norleena Gullett, MD; Elizabeth Kidd, MD; Larissa Lee, MD; Nina A. Mayr, MD; David Moore, MD; Ajmel A. Puthawala, MD; Gautam G. Rao, MD; Mahesh A. Varia, MD; Andrew O. Wahl, MD; Aaron H. Wolfson, MD; William Yuh, MD

Financial Disclosures/Conflicts of Interest

Not stated

Guideline Status

This is the current release of the guideline.

Guideline Availability

Electronic copies: Available from the American College of Radiology (ACR) Web site External Web Site Policy.

Print copies: Available from the American College of Radiology, 1891 Preston White Drive, Reston, VA 20191. Telephone: (703) 648-8900.

Availability of Companion Documents

The following are available:

  • ACR Appropriateness Criteria®. Overview. Reston (VA): American College of Radiology; 2 p. Electronic copies: Available in Portable Document Format (PDF) from the American College of Radiology (ACR) Web site External Web Site Policy.
  • ACR Appropriateness Criteria®. Literature search process. Reston (VA): American College of Radiology; 1 p. Electronic copies: Available in PDF from the ACR Web site External Web Site Policy.
  • ACR Appropriateness Criteria®. Evidence table development – diagnostic studies. Reston (VA): American College of Radiology; 2013 Nov. 3 p. Electronic copies: Available in PDF from the ACR Web site External Web Site Policy.
  • ACR Appropriateness Criteria®. Evidence table development – therapeutic studies. Reston (VA): American College of Radiology; 2013 Nov. 4 p. Electronic copies: Available in PDF from the ACR Web site External Web Site Policy.
  • ACR Appropriateness Criteria® definitive therapy for early stage cervical cancer. Evidence table. Reston (VA): American College of Radiology; 43 p. Electronic copies: Available from the ACR Web site External Web Site Policy.

Patient Resources

None available

NGC Status

This NGC summary was completed by ECRI Institute on August 21, 2012.

Copyright Statement

Instructions for downloading, use, and reproduction of the American College of Radiology (ACR) Appropriateness Criteria® may be found on the ACR Web site External Web Site Policy.

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