Management of locally advanced cervical cancer

INTRODUCTION — Women with locally advanced cervical cancer (stage IB3 to IVA) have a higher rate of recurrence and worse survival than those with early-stage disease (stage IA to IB2). After surgery alone, the rate of relapse is at least 30 percent, and five-year survival rates range from 80 percent for stage IB disease to 30 percent for stage III disease [1,2].

The approach to women with locally advanced cervical cancer is reviewed here. Because the predominant histology of cervical cancer is squamous cell carcinoma, specific issues related to other histologies and other topics relevant to cervical cancer in general are covered elsewhere.

●(See "Management of early-stage cervical cancer".)

●(See "Invasive cervical cancer: Staging and evaluation of lymph nodes".)

●(See "Small cell neuroendocrine carcinoma of the cervix".)

●(See "Invasive cervical adenocarcinoma".)

DEFINITION OF LOCALLY ADVANCED-STAGE CERVICAL CANCER — Following staging, locally advanced cervical cancer is defined by the presence of any of the following findings:

●Confined to the cervix with a clinically visible tumor >4 cm in greatest dimension (stage IB3)

●Invades beyond the uterus but not to the pelvic wall or to the lower third of vagina (stage II)

●Extends to the pelvic sidewall, and/or involves the lower third of vagina, and/or causes hydronephrosis or a nonfunctioning kidney, and/or involves pelvic and/or para-aortic lymph nodes (stage III)

●Invades the mucosa of the bladder or rectum, or extends beyond the true pelvis (stage IVA)

The International Federation of Gynecology and Obstetrics (FIGO) staging system is listed in the table (table 1). The American Joint Committee on Cancer (AJCC) tumor, node, metastasis (TNM) staging system is shown in the table (table 2) [3]. (See "Invasive cervical cancer: Staging and evaluation of lymph nodes".)

PRETREATMENT EVALUATION — All women with cervical cancer should undergo a lymph node evaluation, which impacts stage and treatment [3-5]. For women with locally advanced disease (stages IB3 to IVA) for whom primary chemoradiation is planned, we obtain a positron emission tomography (PET)/computed tomography (CT) scan prior to treatment to evaluate the extent of disease, with particular attention to lymph node metastases to provide information to design radiation fields. (See "Invasive cervical cancer: Staging and evaluation of lymph nodes".)

For women with suspected para-aortic node involvement based on CT scan, some experts proceed with a lymphadenectomy or a CT-guided biopsy for pathologic confirmation of nodal status. At other centers, F-18 fluorodeoxyglucose (FDG) uptake in the para-aortic nodes is sufficient evidence of nodal involvement, and further work-up is not performed. Regardless of whether pathologic confirmation is obtained, treatment is required if para-aortic node involvement is detected. (See "Invasive cervical cancer: Staging and evaluation of lymph nodes", section on 'Surgical evaluation of lymph nodes' and 'Treatment of para-aortic nodes' below.)

Patients with renal insufficiency should undergo imaging to determine whether the etiology is urinary tract obstruction (which is diagnostic of stage III disease) or intrinsic renal disease. Some experts obtain upper urinary tract imaging for all patients with more than a microscopic tumor. In our practice, we obtain non-contrast CT or magnetic resonance imaging if a woman presents with an elevated serum creatinine.

Any urinary tract obstruction should be corrected prior to cancer treatment, especially in patients who are otherwise candidates for primary chemoradiation. In a retrospective study performed by the Gynecologic Oncology Group involving 539 women with stage III cervical cancer (44 percent of whom presented with hydronephrosis) treated with chemoradiation, women who received treatment for ureteral obstruction had a significantly longer progression-free survival (PFS) and median overall survival (OS) than those in whom obstruction was not treated (PFS: median, 18 versus 10 months; OS: median, 34 versus 17 months) [6]. A discussion on the etiology of ureteral obstruction and its management is covered separately. (See "Placement and management of indwelling ureteral stents".)

PRIMARY CHEMORADIATION — For women with locally advanced cervical cancer, we administer primary chemoradiation [7], although we acknowledge that the benefits of treatment are greater with earlier (stage IB to IIB) versus more advanced stage (stage III to IVA).

We do not proceed with primary surgery in women with advanced cervical cancer because surgery is not likely to be curative and these patients usually require adjuvant treatment, which is associated with a high incidence of morbidity [8-10]. In a 2010 study of patients with stage IIB disease treated with primary surgery plus postoperative radiation therapy (RT, n = 34) or primary chemoradiation (n = 25), the rate of serious (grade 3/4) complications was doubled among those treated with primary surgery/RT (26 versus 12 percent) [9].

A 2010 meta-analysis of randomized controlled trials suggested benefit of chemoradiation for women with locally advanced cervical cancer relative to RT alone, although more definitive data are still needed [11]. In this meta-analysis, compared with primary RT, the use of chemoradiation resulted in:

●A reduction in the risk of death (hazard ratio [HR] 0.81, 95% CI 0.71-0.91), which translated into a 6 percent absolute improvement in survival at five years. There was a greater benefit for chemoradiation over radiation in the two trials that gave chemoradiation plus adjuvant chemotherapy (HR 0.46, 95% CI 0.32 to 0.66), which translated into an absolute survival benefit of 19 percent at five years. However, these two trials were relatively small, and had differing designs and limited follow-up. Thus, further data are needed.

In the meta-analysis, additional findings associated with chemoradiation versus RT alone included:

●A reduction in the risk of recurrence (HR 0.78, 95% CI 0.70-0.87), which translated into an 8 percent absolute improvement in progression-free survival (PFS) at five years.

●Statistically significant absolute benefits of chemoradiation versus radiation on five-year locoregional disease-free survival (DFS; 9 percent) and metastases‐free survival (7 percent).

●Higher rates of serious hematologic and gastrointestinal toxicity in trials using platinum-based chemoradiation, but not in trials using non-platinum-based regimens.

Subsequent trials specifically in patients with stage IIIB disease have found both DFS and overall survival (OS) benefits with chemoradiation versus RT alone [12,13].

Chemotherapy regimen — Chemotherapy is usually administered with either single-agent cisplatin or the combination of cisplatin plus fluorouracil (FU) for the treatment of cervical cancer. Of these, we recommend weekly cisplatin (40 mg/m²) during RT [11,14,15]. Single-agent cisplatin administered with RT achieves similar outcomes to cisplatin plus FU and has a better toxicity profile. This was demonstrated in a randomized trial of 155 women with stage IIB to IVA cervical cancer (without para-aortic node involvement) who were randomly assigned treatment with RT plus either cisplatin or cisplatin plus FU [14]. At a median follow-up of 39 months, compared with cisplatin plus FU, treatment with cisplatin resulted in:

●A higher rate of completion of chemoradiation (71 versus 60 percent, respectively)

●Less serious (grade 3/4) hematologic toxicity (26 versus 43 percent)

●Similar complete response rate (91 percent in both arms) and OS rate at four years (67 and 70 percent)

Whether cisplatin in combination with an alternative agent to FU would improve survival outcomes is not clear. A phase III trial that enrolled 515 women compared cisplatin alone with cisplatin plus gemcitabine during concurrent RT [16]. Women randomized to combination chemotherapy also received two additional 21-day cycles of cisplatin plus gemcitabine after completion of RT. With a median follow-up of three years, the use of cisplatin plus gemcitabine resulted in:

●An improvement in PFS compared with cisplatin alone (HR for progression 0.68, 95% CI 0.49-0.95; three-year PFS 74 versus 65 percent)

●An improvement in OS (HR for death 0.68, 95% CI 0.49-0.95)

●But was associated with significantly more serious (grade 3/4) toxicities (87 versus 46 percent) and rate of hospitalizations (30 versus 11)

It is not clear whether the benefits of the investigational treatment were due to the use of cisplatin plus gemcitabine during RT or following chemoradiation. Therefore, we continue to prescribe cisplatin alone during chemoradiation. (See 'No role for systemic chemotherapy after chemoradiation' below.)

Patients with potential contraindications to cisplatin — Cisplatin is associated with significant toxicities, including risks of long-standing neuropathy and potentially chronic renal insufficiency, and patients with chronic or persistent comorbidities (eg, patients with chronic renal failure or severe baseline neuropathy) face a greater risk of experiencing these complications. We prefer to treat these patients with weekly carboplatin dosed at area under the curve (AUC) 2 rather than exposing patients to the nephrotoxic effects of cisplatin. However, decisions regarding the choice of agent to administer with RT should be based on patient and provider preferences.

It is important to note that patients who present with acute organ dysfunction secondary to locally advanced cervical cancer should be worked up for a potentially correctable etiology. For patients with advanced cervical cancer, this most often presents as acute renal failure due to tumor-related hydronephrosis. These patients may experience a normalization of renal function following a ureteral stent or nephrostomy tube placement. Following normalization of renal function, these patients should receive primary chemoradiation with cisplatin. (See 'Primary chemoradiation' above.)

Options for treatment of locally advanced cervical cancer in patients at risk for serious cisplatin-related toxicities are discussed below.

Carboplatin — Based on preclinical data showing that carboplatin is an effective radiosensitizer [17], it is sometimes used in lieu of cisplatin in these patients. However, the data on single-agent carboplatin are limited [18-21].

As an example, in one prospective study, 51 patients with predominantly advanced disease (stage IIB or higher) were treated with carboplatin (100 mg/m²) concurrently with RT [21]. Their outcomes were compared with historical controls comprised of 48 women treated with cisplatin plus RT. Treatment with carboplatin plus RT resulted in:

●A similar overall response rate compared with cisplatin plus RT (90 versus 88 percent, respectively; p = 0.31).

●No difference in survival outcomes at three years. The PFS rate was 78 and 80 percent, respectively (HR 1.21, 95% CI 0.52-2.81); the OS rate was 88 and 94 percent (HR 1.80, 95% CI 0.49-6.54).

●No difference in the incidence of serious (grade 3/4) toxicity.

Gemcitabine — Limited data suggest that gemcitabine may be a reasonable substitute for patients who are unable to receive cisplatin for whatever reason. In a series of nine patients with an obstructive uropathy, chemoradiation was administered with weekly gemcitabine (300 mg/m²); four patients underwent a percutaneous nephrostomy placement prior to chemoradiation [22]. All patients were able to complete treatment, although toxicities were common, including grade 3 neutropenia, dermatitis, proctitis, and colitis. Following treatment, all patients normalized their creatinine. With a median follow-up of 11 months, all patients were alive; two had evidence of recurrent disease.

Beyond these considerations, the limited data suggest that other agents commonly used in cervical cancer should not be administered as a component of primary chemoradiation. This includes:

●FU: Single-agent FU should not be used in this setting; one randomized trial showed that chemoradiation with this agent was no better than RT alone [23].

●Paclitaxel: Concurrent weekly paclitaxel plus RT has only been evaluated in one trial, which enrolled women with either locally advanced or recurrent cervical cancer [24]. Of 13 women with locally advanced disease, eight (62 percent) had a complete response. However, five (26 percent) experienced grade 3 small bowel toxicity, raising questions about whether treatment is feasible.

Radiation therapy — For most women, RT (in conjunction with chemotherapy) is delivered to the pelvis using external beam RT (EBRT). Cervical brachytherapy is also administered in an effort to maximize local control. Two issues that arise in the design of the RT field are the treatment of the para-aortic nodal region and timing of RT treatment. These are discussed below.

Role of brachytherapy — Brachytherapy is the local application of radiation to the cervix/vagina. It is an essential component of treatment for locally advanced cervical cancer and allows for a higher dose of RT to the cervix while sparing the surrounding normal tissue.

Rationale — The importance of brachytherapy was shown in a 2013 study that included over 7000 women with stage IB2 to IVA cervical cancer identified from the Surveillance, Epidemiology, and End Results (SEER) database [25]. Using a matched cohort analysis of patients treated between 2000 and 2009, the use of brachytherapy resulted in significantly higher rates of cancer-specific survival (64 versus 52 percent) and OS (58 versus 46 percent) at four years. Unfortunately, this study also reported a decreased utilization rate of brachytherapy between 1998 and 2009 from 83 to 58 percent, respectively. This decrease in use was seen regardless of stage and histologic type.

A second population-based study from the National Cancer Database analyzed data for 7654 patients treated between January 2004 and December 2011 with stages IIB to IVA cervical carcinoma. This study noted a decrease in use of brachytherapy for the curative treatment of cervical cancer from 97 percent in 2004 to 86 percent in 2011. The authors also reported that in the same time period, use of advanced technologies such as intensity-modulated RT (IMRT) or stereotactic body RT (SBRT) for a boost increased from 3.3 to 14 percent. In a multivariable survival analysis, using IMRT or SBRT for a boost resulted in inferior OS compared with brachytherapy (HR 1.86). This decrease in survival had a higher HR than the survival decrease when chemotherapy was not given (HR 1.56) [26]. In a Quality Research in Radiation Oncology study, the percentage of patients not receiving brachytherapy increased from 6 percent in a 1996 to 1999 survey to 13 percent in a 2005 to 2007 survey. In addition, 65 percent of patients receiving a boost were treated in a facility that treated fewer than three intact cervical cancer patients per year [27,28]. These data highlight the importance of brachytherapy in the treatment of cervical cancer. Given the data demonstrating underutilization, we recommend that these patients be treated at centers where the expertise to perform brachytherapy is available.

Timing and technique — Brachytherapy is initiated during EBRT once optimal tumor reduction is achieved. Adequate cervical regression typically occurs between two and five weeks of therapy depending on presenting tumor stage and size and response to therapy. It can be delivered with either a low-dose rate (LDR), pulse-dose rate (PDR), or high-dose rate (HDR) system. The International Commission on Radiation Units defines LDR brachytherapy as 0.4 to 2 Gy per hour; PDR brachytherapy delivers doses using the HDR source but treating only 10 to 30 minutes at a time, whereas HDR brachytherapy is delivered at >12 Gy per hour. HDR and LDR appear to have similar efficacy and late complications in the management of cervical carcinoma, as suggested by retrospective single-institution reports, randomized trials, and a meta-analysis [29-35]. LDR brachytherapy requires one or two insertions and can begin near or after the completion of EBRT. The number of HDR insertions is variable across institutions, but most commonly is given as three to six insertions. The dose delivered per brachytherapy procedure is adjusted to account for the total number of insertions.

EBRT is delivered once daily for 25 days for a total dose of 45 Gy, usually with 3D conformal therapy. If there is gross nodal disease, a boost to the nodes should be considered interdigitated with the brachytherapy. There is evidence that IMRT can deliver the nodal boost simultaneous to the external beam and better spare normal tissues, but randomized data evaluating the efficacy are pending (image 1 and image 2).

Three techniques can be employed:

●Intracavitary brachytherapy – With intracavitary brachytherapy, a variety of applicators can be employed. These include the placement of an intrauterine tandem with vaginal ovoids, vaginal cylinders, or a vaginal ring (picture 1). The addition of the ovoids or ring to the tandem applicator provides a dose distribution that encompasses the at-risk paracervical tissues while providing a lower-dose distribution to the bladder and rectum. In addition, dose to the bladder and rectum can be reduced further with the use of shielded ovoids and vigorous packing. The choice of applicator is governed by clinician preference and comfort level, as well as patient anatomical considerations. We prefer ovoids, when possible, due to improved dosimetry and dosing to the vaginal fornices and parametria. Vaginal cylinders are employed when distal vaginal disease is present.

●Interstitial brachytherapy – With interstitial brachytherapy, needles are placed with a variety of freehanded and template-based techniques, at times with laparoscopic guidance (picture 2). The most common presentation necessitating the use of interstitial therapy is extensive vaginal involvement. The use of the hybrid approach with a tandem and ring or ovoids with a limited number of needles has been shown to increase the dose to the target and decrease the dose to the organs at risk [36].

●PDR brachytherapy – PDR brachytherapy uses a single Iridium-192 source that is programmed to move through various dwell positions in placed applicators using remote afterloading technology. The movement of the source through the positions constitutes a single pulse, and the dose delivered per pulse; the time interval between pulses and the total pulse duration can be varied. PDR brachytherapy delivers a treatment in which the goal is to draw from the advantages of both HDR brachytherapy and traditional LDR brachytherapy.

Applicator placement typically requires intravenous conscious sedation or general anesthesia for patient comfort. Once the applicators are in place, treatments were traditionally planned using orthogonal radiographs to define prescription and normal tissue points of interest, but this is changing to image-guided brachytherapy using modern imaging such as computed tomography (CT) and magnetic resonance imaging (MRI) (image 3).

Dosing — In the most common brachytherapy planning methodology, the total dose is prescribed to point A, which represents the paracervical tissues (figure 1). The prescribed brachytherapy dose depends on tumor stage, initial disease bulk and response to pelvic RT, ability to displace bladder and rectum, and use of LDR, HDR, or PDR technique. The total prescription dose to point A is 80 to 90 Gy LDR equivalent, depending on tumor stage [37,38]. A biologically effective dose is calculated and used when comparing HDR and LDR brachytherapy. The choice of dose for HDR also depends upon the number of fractions, for which there are multiple accepted regimens [38]. We prescribe a total brachytherapy dose of 27.5 Gy in five fractions when given with concurrent chemotherapy, or with a good response to external therapy; or 30 Gy in five fractions with RT alone, or with a poor response to chemotherapy. Another commonly used regimen is four fractions of 7 Gy.

Image-guided adaptive brachytherapy — Three-dimensional techniques with CT- or MRI-based brachytherapy planning is used in some institutions to escalate the dose to the target while accurately assessing the dose delivered to surrounding tissue at risk for toxicity. The use of this technique, called image-guided adaptive brachytherapy (IGABT), is increasing as experience and data regarding its efficacy become available [39-43].

As an example, in a prospective cohort study, among 1341 patients with locally advanced cervical cancer, MRI-based IGABT was associated with a five-year local control rate of 92 percent; five-year incidence of grade ≥3 morbidity was 6.8 percent for genitourinary events, 8.5 percent for gastrointestinal events, 5.7 percent for vaginal events, and 3.2 percent for fistulae [44,45].

Data suggest improvements in toxicity with IGABT relative to conventional techniques. In a randomized trial including 300 patients with cervical cancer receiving adjuvant pelvic radiation and vaginal brachytherapy, the three-year cumulative incidence of grade ≥2 gastrointestinal toxicity was 21 percent with image-guided brachytherapy versus 42 percent with conventional brachytherapy (HR 0.46, 95% CI 0.29-0.73) [46]. The incidence of grade ≥2 any late toxicity was 28 versus 49 percent, respectively (HR 0.50, 95% CI 0.33-0.76). The three-year DFS rates in the image-guided intensity-modulated RT versus the three-dimensional conformal RT arm were 77 versus 81 percent (HR 1.03, 95% CI 0.62-1.71, respectively).

Observational studies have similarly suggested improvements with IGABT over conventional brachytherapy in regards to toxicity, without compromising disease outcomes [42,47-50]. One prospective study including over 200 patients with advanced cervical cancer treated with chemoradiation followed by either IGABT or conventional brachytherapy found that IGABT was associated with an improvement in two-year locoregional control rate (70 versus 61 percent) and a reduction of grade 3 to 4 morbidity (1 versus 14 percent) when compared with conventional brachytherapy [47]. A nonsignificant trend towards improved survival was also observed (74 versus 65 percent, respectively). Data from ongoing prospective studies will provide further insight to the relative benefits and risks associated with IGABT.

Treatment of para-aortic nodes — Women with evidence of para-aortic node involvement have a poor prognosis with a five-year survival rate of approximately 40 percent [51]. Despite low-quality data, it is routine practice to treat these patients with extended field RT. This entails extending the superior pelvic field border to the level of the T12 to L1 disk space in order to include the para-aortic nodes (image 4).

There are no trials that compare chemoradiation using extended field RT (to cover the para-aortic region) versus pelvic RT, but given their high risk of disease progression and death, we prefer to treat these women with extended field RT with concurrent cisplatin. However, it is critical that women be counseled that such treatment is associated with a high risk of serious acute and late toxicity [52-55]. Many centers have chosen to use IMRT, at least to the para-aortic nodal region, to decrease morbidity and allow dose escalation to the involved nodes.

In the largest study, the Gynecologic Oncology Group enrolled 95 women with histologically confirmed para-aortic node metastases and treated them with concomitant chemoradiation using extended field RT and reported the following results [53]:

●The three-year OS and PFS rates for the entire group were 39 and 34 percent, respectively.

●The rate of grade 3 or higher gastrointestinal toxicity was 19 percent, likely due to a lower dose to the para-aortic region used in this study compared with the Radiation Therapy Oncology Group (RTOG) study.

●The rate of late morbidity at four years was 14 percent.

These data suggest that disease control can be attained in some women with locally advanced cervical cancer. However, treatment is associated with a high rate of acute and late toxicity.

In another small, single-institution, prospective study, the treatment of para-aortic node metastases with IMRT was compared with conventional para-aortic field RT [56]. Compared with conventional RT, IMRT resulted in:

●Significantly higher rates of tumor response and OS at two and three years

●Less hematologic and gastrointestinal toxicity, although a higher dose was delivered with IMRT to the nodes.

Given the lack of data that prophylactically extending the RT field in women without para-aortic node involvement improves outcomes, the acute and late toxicity risks of extended-field RT must be taken into consideration. Therefore, we suggest not administering full extended-field RT for women without evidence of para-aortic node involvement, although extension of the upper border of the field by 5 cm above the last gross nodal disease (or to the level of the renal vessels) detected is often advised.

Importance of time to completion of chemoradiation — For all women undergoing chemoradiation, treatment should be completed within eight weeks. Although older studies demonstrated the importance of the timely completion of RT [57-59], there are limited data on the importance of time to completion for women undergoing chemoradiation, but the preponderance of data would suggest that even with chemoradiation, treatment should be competed in seven to nine weeks. [59-61].

In one series of 113 women with stage IB to IIIB disease, with a median follow-up of 26 months, time to completion of brachytherapy >56 days was associated with a higher rate of disease progression within the pelvis (26 versus 9 percent; HR 2.8, 95% CI 1.2-16) [60]. However, the time to completion of chemoradiation was not a significant factor for distant disease progression or disease-specific mortality. Two other studies at this time demonstrated that prolongation of treatment beyond seven weeks resulted in decreased pelvic control rates of 0.7 to 0.85 percent per day of prolongation and an 0.6-percent reduction in survival [57,62].

Another study of 480 women evaluating treatment duration with and without chemotherapy suggested that with RT alone, treatment duration greater than or equal to 62 days may impact DFS [63]. When chemoradiation therapy was administered, treatment duration did not predict for in-field relapse, DFS, or OS. A subsequent review of this issue evaluated patients with advanced cervical cancer treated between 2003 and 2011, and 95 percent were treated with concurrent chemoradiation [64]. Prolonged duration of treatment (>10 to 12 weeks) was associated with worsened DFS and OS.

Role of hysterectomy after chemoradiation — Some surgeons perform a simple extrafascial hysterectomy following chemoradiation in select patients with disease characteristics that suggest a higher risk of relapse (eg, initially large cervical lesion >7 cm, lower uterine segment involvement, or those with post-treatment residual disease). However, there is no evidence that doing so improves survival outcomes in this population, and most centers do not routinely perform hysterectomy following chemoradiation.

There are few high-quality data regarding this issue [65-67]. In a randomized trial including 61 patients with stage IB2 to II cervical cancer who had a complete clinical and radiologic response after primary treatment with chemoradiation, those assigned to hysterectomy compared with no hysterectomy had similar event-free survival and OS at three-year follow-up [65].

No role for systemic chemotherapy after chemoradiation — We suggest not administering systemic chemotherapy for women completing primary chemoradiation, as there is limited evidence of benefit to justify the additional toxicity risks.

In a randomized trial including 919 patients with locally advanced cervical cancer, those assigned to standard cisplatin-based chemoradiation followed by four cycles of adjuvant carboplatin and paclitaxel experienced similar OS at five years as those assigned to concurrent chemoradiation only (72 versus 71 percent; HR 0.90, 95% CI 0.70-1.17) [68]. PFS at five years was also similar between the groups (63 versus 62 percent; HR 0.86, 95% CI 0.69-1.08). Grade ≥3 adverse events within a year of randomization occurred in 81 versus 62 percent, respectively.

By contrast, in an earlier trial, women who received two cycles of systemic intravenous cisplatin plus gemcitabine after chemoradiation had significant improvements in both PFS and OS compared with women who received cisplatin-alone-based chemoradiation and no further chemotherapy [16]. However, as discussed above, it is not clear if the survival benefit was due to combination chemotherapy delivered with RT, following RT, or both. In addition, the Gynecologic Oncology Group ran a similar trial of gemcitabine followed by cisplatin with concomitant RT, but this trial was stopped due to excessive grade 3/4 toxicities [69].

Given the concerns for toxicity and the unclear contribution of systemic treatment, we do not administer further treatment after chemoradiation.

NEOADJUVANT CHEMOTHERAPY — Neoadjuvant chemotherapy prior to definitive hysterectomy does not offer an overall survival (OS) advantage relative to primary chemoradiation, and in randomized trials discussed below, it has been associated with inferior disease-free survival (DFS). Therefore, in geographic areas where chemoradiation can be performed, we prefer to administer chemoradiation rather than neoadjuvant chemotherapy for locally advanced cervical cancer. However in parts of Europe, Asia, and South America where access to radiotherapy facilities is limited, neoadjuvant chemotherapy before surgery is an appropriate option for women with locally advanced disease.

In a phase III trial, 633 women with stage IB2, IIA, or IIB squamous cervical cancer were randomly assigned to either three cycles of neoadjuvant chemotherapy (paclitaxel and carboplatin once every three weeks) followed by radical hysterectomy or to standard chemoradiation. Compared with standard chemoradiation, those receiving neoadjuvant chemotherapy followed by surgery experienced worse five-year DFS (69.3 versus 76.7 percent, respectively; hazard ratio [HR] 1.38, 95% CI 1.02-1.87) [70]. However, five-year OS was similar between the two groups (75.4 versus 74.7 percent, respectively; HR 1.025, 95% CI 0.75-1.40). Delayed toxicities at two years or later after treatment completion were worse in the group treated with chemoradiation compared with neoadjuvant chemotherapy, and included rectal (3.5 versus 2.2 percent, respectively), bladder (3.5 versus 1.6 percent), and vaginal (25.6 versus 12.0 percent) complications.

In preliminary results of a separate phase III trial (European Organisation for Research and Treatment of Cancer [EORTC] 55994), among 620 patients with stage IB2 to IIB cervical cancer, those randomly assigned to neoadjuvant chemotherapy followed by surgery experienced worsened five-year progression-free survival rates (57 versus 66 percent; difference 9 percent, 95% CI 2 to 18 percent) and comparable five-year OS rates (72 versus 76 percent; HR 0.87, 95% CI 0.65-0.15) as those receiving concomitant chemoradiation [71]. While short-term grade ≥3 toxicities were higher with neoadjuvant therapy followed by surgery (41 and 23 percent, respectively), long-term toxicities were less frequent compared with chemoradiation (15 versus 21 percent).

POST-TREATMENT IMAGING AND SURVEILLANCE — We obtain positron emission tomography (PET)/computed tomography (CT) three to four months following therapy for its prognostic value. The main goal of subsequent post-treatment surveillance is early detection of those recurrences that might be amenable to potentially curative therapy. The optimal surveillance strategy has not been established. Consensus-based guidelines for post-treatment surveillance are discussed separately. (See "Invasive cervical cancer: Patterns of recurrence and post-treatment surveillance", section on 'Surveillance strategies'.)

In a study of 238 patients with cervical cancer treated with chemoradiation, all patients had a pretreatment fluorodeoxyglucose positron emission tomography (FDG-PET) and a post-therapy FDG-PET 8 to 16 weeks after treatment completion. Among these patients, 38 percent experienced a recurrence [72]. The rate of recurrence among those with complete metabolic response, partial metabolic response (PMR), and progressive disease was 23, 65, and 100 percent, respectively, differences that were statistically significant. While most failures were distant, a PMR predicted for locoregional failure. Of those recurring after a PMR on post-treatment PET, 42 percent had a component of distant disease versus 96 percent among those with progressive disease.

QUALITY OF LIFE CONSIDERATIONS — Cervical cancer treatment may have a negative impact on quality of life, which can persist for years following treatment, particularly among women who were previously treated with radiation therapy [73-75]. This issue is discussed in detail separately. (See "Management of early-stage cervical cancer", section on 'Long-term quality of life'.)

PROGNOSIS — The major prognostic factors affecting survival are stage, nodal status, tumor volume, depth of cervical stromal invasion, lymphovascular space invasion (LVSI), and to a lesser extent, histologic type and grade. A summary of survival rates by stage of disease according to the latest International Federation of Gynecology and Obstetrics (FIGO) data is available (table 3) [76].

Women with locally advanced cervical cancer have a higher rate of recurrence and worse survival than those with early-stage disease. After surgery alone, the rate of relapse is at least 30 percent [1,2]. According to statistics from the American Cancer Society, the five-year survival rate by stage is [77]:

●Stage IB – 80 percent

●Stage IIA – 63 percent

●Stage IIB – 58 percent

●Stage III – 30 percent

●Stage IVA – 16 percent

Human papillomavirus status may also affect prognosis. This is discussed in detail separately. (See "Management of early-stage cervical cancer", section on 'Prognosis'.)

SPECIAL CONSIDERATIONS

Incidentally diagnosed cancer — In rare instances, women who undergo a simple hysterectomy for what was thought to be cervical intraepithelial neoplasia (or for another benign indication) have a final pathology result showing cervical cancer. For women in this situation, we suggest a radical parametrectomy and upper vaginectomy with lymph node evaluation or chemoradiation. Single-institutional studies have shown that radical parametrectomy is feasible and results in recurrence rates between 0 to 11 percent and a five-year overall survival rate over 96 percent [78-80].

Adjuvant chemoradiation may be a reasonable alternative to further surgery for women who are not candidates for radical pelvic surgery or those with disease that cannot be easily encompassed by a radical parametrectomy. However, a retrospective study involving 147 patients with occult invasive cervical cancer suggests patients treated with this approach have a higher rate of recurrence compared with those treated with radical parametrectomy (7 versus 0 percent) [79]. In addition, chemoradiation resulted in a 27 percent rate of late complications related to radiation therapy (RT). (See "Management of early-stage cervical cancer", section on 'Indications'.)

Women who are poor candidates for primary chemoradiation — We perform a primary modified radical hysterectomy in select patients with stage I disease (<4 cm tumor) who are not candidates for chemoradiation. This includes the following:

●Women with acute or chronic pelvic inflammatory disease in whom chemotherapy is a relative contraindication (see "Pelvic inflammatory disease: Clinical manifestations and diagnosis")

●Women with a coexistent pelvic mass that is suggestive of a dual malignancy

●Women with anatomic alterations that make optimal RT difficult

●Women in whom compliance with RT would be difficult

In one study, these criteria were used to select 95 women with stage IB cervical cancer for primary surgery [81]. The five-year survival rate in this highly selected group was 91 percent.

For women who are not surgical candidates, we suggest primary RT alone.

Considerations during the COVID-19 pandemic — The COVID-19 pandemic has increased the complexity of cancer care. Important issues in areas where viral transmission rates are high include balancing the risk from treatment delay versus harm from COVID-19, ways to minimize negative impacts of social distancing during care delivery, and appropriately and fairly allocating limited health care resources. These and other recommendations for cancer care during active phases of the COVID-19 pandemic are discussed separately. (See "COVID-19: Considerations in patients with cancer".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Treatment of cervical cancer".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Beyond the Basics topics (see "Patient education: Cervical cancer treatment; early-stage cancer (Beyond the Basics)" and "Patient education: Fertility preservation in early-stage cervical cancer (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Definition of locally advanced-stage cervical cancer – Locally advanced cervical cancer is defined as: disease confined to the cervix with a clinically visible tumor >4 cm (stage IB3); disease that invades beyond the uterus, but involves less than the upper two-thirds of the vagina (stage II); disease that extends to the pelvic sidewall, involves the lower third of vagina, and/or causes hydronephrosis or nonfunctioning kidney (stage III); or disease that extends to the rectum or bladder, or beyond the true pelvis (stage IVA (table 1)). (See 'Definition of locally advanced-stage cervical cancer' above.)

●Primary chemoradiation – For women with locally advanced cervical cancer, we suggest primary chemoradiation rather than primary surgery, neoadjuvant chemotherapy followed by surgery, or radiation therapy (RT) (Grade 2B). We acknowledge that there are greater benefits to treatment for women with earlier-stage (stage IB to IIB) rather than later-stage (stage III to IVA) disease. We suggest weekly cisplatin during RT rather than combination chemotherapy (eg, cisplatin plus fluorouracil) during RT (Grade 2B). (See 'Primary chemoradiation' above.)

●Pretreatment evaluation – We perform a positron emission tomography (PET)/computed tomography (CT) in all patients with locally advanced cervical cancer in order to define the extent of disease and evaluate the pelvic and para-aortic lymph nodes. (See 'Pretreatment evaluation' above.)

●Approach to para-aortic nodes – For women with a positive PET/CT scan showing para-aortic node involvement, some experts perform a lymphadenectomy or CT-guided biopsy for pathologic confirmation. Other experts do not perform further evaluation if the PET/CT scan is positive. (See 'Pretreatment evaluation' above and 'Treatment of para-aortic nodes' above.)

•For women with suspected or pathologically confirmed para-aortic node involvement, we suggest primary chemoradiation with extended-field RT (Grade 2C). However, consideration of the risks of treatment should be discussed with patients.

•We suggest not administering full extended-field RT for women without known or suspected para-aortic node involvement (Grade 2C).

●Role of hysterectomy after chemoradiation – We suggest not performing a post-treatment hysterectomy following primary chemoradiation (Grade 2C). However, some experts offer patients with an initially large cervical lesion (>7 cm), lower uterine segment involvement, or a high post-treatment residual tumor volume a simple hysterectomy at the completion of treatment. (See 'Role of hysterectomy after chemoradiation' above.)

●Post-treatment surveillance – Following primary treatment with curative intent, patients are monitored serially with history and physical examination and Pap smears. For prognostic purposes, we obtain a PET/CT three to four months following completion of therapy. We reserve subsequent surveillance imaging only if a recurrence is suspected. (See 'Post-treatment imaging and surveillance' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Jennifer F De Los Santos, MD, who contributed to an earlier version of this topic review.