Radiation oncology management of stage III and IVA cervical carcinoma

Abstract

Worldwide, stage III–IVA carcinomas of the uterine cervix comprise a significant proportion of cases at presentation, and have a higher rate of recurrence and worse overall survival. This review will discuss the epidemiology, prevention strategies, clinical presentation, and treatment recommendations for stage III–IVA cervical cancer. The focus will be on the role of radiation therapy, concurrent chemoradiotherapy, and brachytherapy, including the potential benefits and anticipated toxicities. The unique challenges and considerations of fistula formation and approaches to management will be highlighted, and follow-up care and future directions discussed. As low and middle income countries bear the highest burden of advanced stage carcinoma of the uterine cervix, this review will address the unique needs of global communities.

INTRODUCTION

Incidence and Epidemiology

Cervical cancer is the fourth most common cancer and the fourth leading cause of cancer death in women worldwide. The global annual incidence of cervical cancer in 2020 was 604 000 new cases and there were 342 000 estimated cancer deaths.¹ Cervical cancer risk factors include those related to risk of human papillomavirus (HPV) infection, and non-HPV related risk factors including a smoking history, which has also been associated with fistula formation in locally advanced disease.² Globally, the average age of death of women with cervical cancer is 59, with older women more likely to be diagnosed with advanced stage disease. Higher recurrence rates and worse survival are seen in women with stage III–IVA cervical cancer, with a five year survival of 39.7%–41.5% for stage III disease and 22% for stage IVA disease.³ These data are of particular interest to the global community because resource-limited regions of low and middle income countries account for 85% of cases and 88% of deaths worldwide.⁴

Presentation, Symptoms, and Signs of Advanced Disease

In advanced stage III–IVA cervical cancer, patients often present with hematuria, abnormal vaginal or postcoital bleeding, malodorous vaginal discharge, dyspareunia, and pelvic or back pain. In cases with invasion of the pelvic sidewall causing hydronephrosis or hydroureter, presentation can include the triad of lower limb edema, flank pain, and sciatica. Passage of urine or feces through the vagina is rare and can be due to vesicovaginal or rectovaginal fistulas, respectively.

Diagnostic Investigation

Clinical evaluation, through a comprehensive history and physical exam, is the first step in the diagnostic investigation of any patient presenting with signs or symptoms concerning for advanced cervical cancer. Staging is paramount in helping determine the volume and extent of disease, optimizing the design of the treatment area for delivery of radiation therapy. National Comprehensive Cancer Network guidelines recommend a complete blood count, cervical biopsy with pathological review, liver function and renal function studies, smoking cessation and counseling intervention if indicated, imaging, and HIV testing, exam under anesthesia, cystoscopy/proctoscopy, and discussion on fertility considerations, as needed.

Advanced stage III–IVA cervical cancer is a complex mix of multiple disparate presentations. Before 2018, International Federation of Gynecology and Obstetrics (FIGO) staging included findings from physical examination, cervical biopsy, endoscopy, and imaging studies, including intravenous pyelogram, chest radiograph, and bone scan. In 2018, the FIGO screening guidelines were revised to allow for more advanced imaging and pathological findings, emphasizing the central importance of imaging in appropriate patient management.

The 2018 FIGO staging system includes minor changes to the definition of stage IIIC disease. Stage IIIA, which involves the lower third of the vagina, with no extension to the pelvic wall, and stage IIIB, which includes extension to the pelvic sidewall or involving the lower third of the vagina causing hydronephrosis or non-functioning kidney, remain the same. The newly added stage IIIC is defined by the presence of nodal metastasis on imaging, independent of tumor size and extent, including IIIC1 with pelvic lymph nodes and IIIC2 with para-aortic lymph nodes. However, the new stage IIIC does not define the extent of the primary tumor. The new staging system permits use of imaging modalities, including positron emission tomography (PET), computed tomography (CT), and magnetic resonance imaging (MRI) to define disease extent. Stage IVA includes invasion of the mucosa of the bladder or rectum, extending beyond the true pelvis.⁵ Although a retrospective validation of the new FIGO staging system using the United States Surveillance, Epidemiology, and End Results (SEER) cohort data from 1988 to 2014 supported the benefit and utility of the revised FIGO staging system in earlier stages, outcomes were heterogeneous for stage IIIC, probably limited by the lack of detailed information on degree of lymph node involvement, a key features of stage IIIC.⁶ Additional prospective studies will be needed to fully capture the impact of the updated FIGO staging system.

The Changing Role of Imaging

Imaging, now incorporated into the FIGO staging system, includes utilization of PET/CT (Figure 1) and MRI (Figure 2). The importance of imaging modality, including the sensitivity and specificity, in addition to operator experience, is important in stage III–IVA cervical cancer to optimally direct treatment while minimizing morbidity and mortality. These more advanced imaging technologies can be optimally used in stage III–IVA disease to better assess involvement of the pelvic and para-aortic region, degree of local extension/invasion, and evaluation of distant metastasis. Optimal imaging allows treatment plans to be adapted to anatomy and disease extent.

Figure 1.

Positron emission tomography/computed tomography scan in a patient with a history of a supracervical hysterectomy, presenting with hematuria. PET demonstrates bladder involvement (arrow) extending from an enlarged cervico-vaginal mass. treatment included 45 Gy to the pelvis and inguinal lymph nodes with concurrent cisplatin chemotherapy followed by template-based interstitial brachytherapy.

Figure 2.

Bladder involvement might encompass the entire organ or be limited to one small region. Axial and sagittal T2-weighted magnetic resonance images show bladder involvement (arrows) in the patient seen in Figure 1.

MRI has been shown to have a high diagnostic accuracy to rule out the presence of bladder or rectal involvement, with negative predictive values of 96%–100%, providing a non-invasive approach to select patients at risk of stage IVA disease who should undergo cystoscopy and endoscopic examination.⁷ The incorporation of advanced imaging for staging is therefore an important consideration in preventing unnecessary invasive procedures, and should be considered when such resources are available.

In addition, image guided detection of para-aortic nodal disease can result in subsequent treatment modification to extended field radiotherapy. A systematic review published in 2020 showed that at the highest prevalence, the positive predictive value and negative predictive value of [18F] fluorodeoxyglucose (FDG)-PET/CT showing lymph node metastases in patients with locally advanced cervical cancer were 0.86 and 0.61.⁸ Previous meta-analysis evaluating FDG-PET/CT showed pooled sensitivity ranging from 72% to 82% and specificity from 95% to 98%.^9–12 In contrast, alternative imaging strategies such as MRI and CT have reported a pooled sensitivity and specificity of 56% and 91%, and 50% and 92%, respectively.⁹

The moderate sensitivity in PET/CT has brought into question the best staging approach for para-aortic lymph nodes. The Uterus-11 prospective international multicenter study of patients with FIGO 2009 stage IIB–IVA cervical cancer randomized patients 1:1 to surgical staging versus clinical staging followed by primary platinum-based chemoradiation. No difference was seen in disease free survival.¹³ Laparoscopic staging led to upstaging in 39 of 120 (33%) patients, a finding that was also seen in a retrospective multicenter study of laparoscopic extraperitoneal para-aortic staging in locally advanced cervical cancer, where extended field radiation therapy was required in 34% of patients from the surgical group.¹⁴ This finding was also similar to that seen when evaluating the clinical impact of FDG-PET/CT on the management of locally advanced cervical cancer; imaging resulted in altered management in approximately one-third of patients.¹⁵ An ongoing trial, lymphadenectomy in locally advanced cervical cancer (LiLACS), will prospectively determine whether pre-therapeutic laparoscopic surgical staging followed by tailored chemoradiation improves survival compared with PET/CT radiological staging alone, followed by chemoradiation.¹⁶

Renal Insufficiency

In patients with renal insufficiency, urological evaluation with imaging can be helpful in assessing the underlying pathophysiology. Determining the primary mechanism could help guide the best therapeutic approach. If obstruction is secondary to tumor, stent placement or percutaneous nephrostomy tube placement can be used to relieve the ureteral obstruction. This approach has been shown to significantly impact progression free survival and median overall survival in patients with stage IIIB cervical cancer treated with concurrent radiation and chemotherapy.¹⁷ In stage IVA disease, temporary placement of a foley or self-catheterization can be one option to manage symptoms in the setting of bladder invasion.

Fistula Formation in Stage IVA Cervical Carcinoma

In more advanced stages of cervical cancer, particularly FIGO stage IVA, invasion of the bladder or rectum portend a high risk in the development of vesicovaginal or rectovaginal fistulae. Data on fistula formation and subsequent resolution, either spontaneous or though surgical intervention, are lacking. Limited studies exist evaluating factors that can be used to identify patients at higher risk of developing such complications, and use of predictors to help guide management. One reason is the exceedingly rare presentation of late-stage disease invasive of surrounding tissue, particularly in the setting of improved prevention and detection. The global impact, however, continues to be more pronounced, and the associated morbidity and mortality are such that further studies and improved understanding of the available literature are warranted. Although stage IVA cervical cancers account for only 1.7%–5% of cases, vesicovaginal fistulae make up almost a quarter of the documented urinary toxicities.

Fistulae formation during the course of chemoradiotherapy can be due to tumor regression in the setting of response to treatment, particularly if there is initial tumor invasion of the rectovaginal septum or bladder wall. Fistulae can also occur 6–24 months after treatment completion due to tissue ulceration in the setting of tissue inflammation and hypoxia. There is an increased risk based on radiation dose and history of vascular disease in the setting of known risk factors, such as diabetes, smoking, and hypertension. Previous abdominal or pelvic surgery can also increase the risk of fistulae formation.¹⁸ Ultimately, post-radiation vesicovaginal fistulae pose a complex urological problem, compromising the success of surgical repair due to poor vascularity and impaired tissue healing. Rectovaginal fistulas can be highly debilitating and impact quality of life. An upfront discussion of the potential worsening of initial fistulae over the course of treatment, and the possibility of radiation induced fistulae after treatment completion, is important in managing patient expectations and improving shared decision-making between patients and providers. Local care including drainage of untreated collections, use of antibiotics, seton placement, and treatment of inflammation can be provided to allow tissue healing. Stool diversion can allow for treatment completion and wound healing before definitive surgical intervention and could also allow for fistulae to ultimately heal on their own. Surgical approach is dictated by fistula location and etiology, though multiple approaches may be required. Management methods can range from conservative approaches such as prolonged catheterization, or surgical interventions such as colostomy, cystectomy, ileocytoplasty, and myocutaneous rectus abdominus flaps.^19–21 Due to the exceedingly small number of cases, the existing literature consists of single case studies, small case series, or retrospective reviews with small sample sizes, bringing into question the validity of such small numbers. In situations where spontaneous healing does not occur, a plastics flap can be attempted. However, in patients with inoperable disease or with subsequent recurrence, the chronic, lifelong presence and associated morbidity of a fistula is a strong possibility that warrants consideration in weighing different treatment approaches.

Two single center retrospective reviews have evaluated fistulae formation in patients with stage IVA cervical cancer. The University of Oklahoma Health Sciences Center found that, of the 23 patients diagnosed with stage IVA disease between 1994 and 2004, all had extension of disease into the bladder, with one having additional invasion into the rectum. This study found that almost half (47.8%) developed a fistula at a median time of 2.9 months from diagnosis. Smokers were found to have significantly higher rates of severe complications (28% vs 15.2%; p<0.01). In this study, 60.8% underwent concurrent chemotherapy and radiation, 30.4% underwent radiation alone, and 8.7% elected for no treatment.²² Post-radiation vesicovaginal fistulae were difficult to repair, possibly due to poor vascular supply and poor wound healing. In another study from the Netherlands, 30 patients (2.4%) from a cohort of 1251 were diagnosed with stage IVA cervical cancer from 1992 to 2008. Of these, 27 (90%) had tumor extension into the bladder, of which two had additional extension into the rectum, and three (10%) had only rectal involvement. Twenty-three patients (77%) underwent curative intent treatment. Eighteen (60%) received radiotherapy with or without chemotherapy and/or hyperthermia, while 5 (17%) were treated with radiation alone. Seven patients (23%) received only palliative therapy or no treatment. Of the definitively treated patients, five (22%) were diagnosed with one or more fistulae (three vesicovaginal, one rectovaginal, and one vesicovaginal and rectovaginal fistulae), with four (17%) developing a fistula after treatment, and one patient (4%) having a fistula present at initial diagnosis. The time to diagnosis of fistula ranged from 0 to 25 months and those definitively treated had a 5 year overall survival of 42%, compared with 32% for the entire cohort. The 3 year fistula free survival was 64%.²³ Although the numbers for fistula formation in this study were lower than those seen in the previously mentioned study by Moore and colleagues, they were in line with other retrospective reviews reporting a fistula formation rate of 22%.²⁴ A small, single institutional retrospective review of 12 patients with stage IVA cervical cancer treated with external beam radiation therapy, concurrent chemotherapy, and image-guided brachytherapy found that two (20%) of 10 had resolution of the fistula/adjacent organ invasion, with eight (80%) not experiencing resolution after radiation.²⁵ Patients that fared best were managed with percutaneous nephrostomy tubes from diagnosis to ensure that no urine leakage through the fistula occurred during treatment. Persistent leakage through the fistula causes persistent opening of the fistula, infection that may spread, and leads to poor wound healing and subsequent irreparable damage to adjacent soft tissue and bone. Once chemoradiation and brachytherapy are complete, surgical assessment is needed to determine whether an ileal conduit or other bladder reconstruction are required urgently, or whether persistent wound issues will require plastics flap closure. If left untreated, surgical debridement, hyperbaric oxygen, and ultimately diversion will be required. Hyperbaric oxygen can help decrease pain and stimulate healing; to the amount the tissue is able to heal. In that regard, hyperbaric oxygen treatment can be helpful. Unfortunately, not all patients are able to tolerate treatment with hyperbaric oxygen, and the degree of usefulness can vary depending on the baseline repair potential of the affected tissue. Close follow-up by a collaborative surgical management team including gynecological oncology, urology, plastic surgery, and other providers is essential for high quality care.

The high rate of subsequent fistula formation after external beam radiation therapy in patients with initial organ involvement but not symptomatic fistula highlights the importance of clear communication between patients and physicians in setting appropriate expectations. Toxicities and side effects caused by treatment of locally advanced cervical cancer are important to consider and discuss with patients at initial consultation, with special attention to both acute and long-term complications, in the context of disease free and overall survival. Patients must be prepared for requirements for ostomies (stool and urine), wound care, frequent interventions, antibiotics, and other complex medical needs.

Treatment

Standard of care for the treatment of locally advanced cervical cancer is definitive cisplatin-based chemotherapy, given concurrently with radiotherapy to include both external beam radiation therapy and brachytherapy, delivered over 8 weeks.²⁶

A meta-analysis of individual patient data from 13 randomized trials showed an absolute survival benefit of 6% and a disease free survival benefit of 8% over 5 years with concurrent chemoradiotherapy.²⁷ However, a decreasing benefit was seen in the effect of chemoradiotherapy on survival with increasing tumor stage, with only a 3% difference seen in stage III to stage IVA at 5 years. These findings prompted two phase III randomized clinical trials looking specifically at cisplatin chemoradiotherapy versus radiotherapy alone for FIGO stage IIIB squamous cell carcinoma of the cervix. After 63 month median follow-up time, a significant benefit in disease free survival and overall survival in the cervical radiation therapy group was seen.^{28 29} Similar findings were reported by Shrivastava and colleagues in the cisplatin chemoradiation versus radiation in FIGO stage IIIB squamous cell carcinoma of the uterine cervix (CRACx trial). This single institution randomized clinical trial showed statistically significant superior disease free survival and overall survival, even after adjusting for prognostic factors, in women with stage IIIB cervical cancer treated with concurrent chemoradiation versus radiation alone. Their study showed an absolute benefit of 8.5% in disease free survival and 8% in overall survival.³⁰ This trial definitively proved the benefit of concurrent chemotherapy and radiation in patients with FIGO stage IIIB cervical cancer.

The Role of Outback Chemotherapy

Dueñas-González and colleagues conducted a randomized trial analyzing the role out of concurrent and outback gemcitabine/cisplatin chemotherapy, and showed a survival advantage primarily in the stage III–IVA subset of patients.^{31 32} This led to the question of whether the combination of the more commonly used carboplatin/taxol regimen would provide a similar benefit. The OUTBACK trial (RTOG 1174), an international phase III randomized trial of the Gynecologic Cancer InterGroup (GCIG), evaluated the question of standard chemoradiation with weekly cisplatin versus the addition of four cycles of carboplatin and paclitaxel given in the extended adjuvant setting for locally advanced cervical cancer (FIGO 2008 stage IB1 and node positive, IB2, II, IIIB, or IVA). The primary endpoint was 5 year overall survival with secondary endpoints including progression free survival, adverse events, and patterns of disease recurrence. Results presented during the 2021 ASCO Annual Meeting did not separate the stage III or IVA subgroups. For all stages together in 919 participants, there was no benefit for outback chemotherapy.³³ With a median follow-up of 60 months, 5 year overall survival was 71% versus 72% in the control versus intervention group, with a hazard ratio of 0·91 (95% CI 0.70 to 1.18). Progression free survival at 5 years was also similar at 61% versus 63% with a hazard ratio of 0·87 (95% CI 0.70 to 1.08). The grade 3–5 adverse events within the first year of randomization were higher in the intervention group at 81% versus 62% in the control group, without differences past the 1 year mark. Although the results were negative, an interesting finding was that outcomes for both groups were better than expected with previous studies, showing a 5 year overall survival of 54% versus 71%. Table 1 provides additional information on selected trials of various treatment modalities for advanced stage III–IVA cervical cancer.

Table 1.

Selected trials of various treatment modalities for advanced stage III–IV cervical cancer.

Trial	Years	Treatment type (n)	International Federation of Gynecology and Obstetrics stage (III/IVA)	Outcome
Fagundes et al*	1959–1986	Radiation therapy alone	III 292 (39%) IVA 20 (75%)	10 year actuarial failure in the pelvis only 56 (19%) 4 (20%)	10 year actuarial total distant metastasis 115 (39%) 15 (75%)
RTOG 9001	1990–1997	Extended Field (Pelvic + Para-Aortic) Radiation Therapy alone (59) Pelvic radiation therapy + chemotherapy (59)	III 110 (57 radiation therapy/53 chemo + radiation therapy) IVA 8 (2 radiation therapy/6 chemo + radiation therapy)	5 year disease free survival III-IVA (37%) III-IVA (54%)	5 year overall survival III-IVA (45%) III-IVA (59%)
Shirvastava et al	2003–2011	Radiation therapy alone (426) Chemotherapy + radiation therapy (424)	IIIB	5 year disease free survival 43.8% 52.3%	5 year overall survival 46% 54%
Retro-EMBRACE	2010–2013	External beam radiation therapy±chemotherapy+CT or MRI based brachytherapy	III 168 (22.9%) IVA 23 (3.1%)	Actuarial 5 year pelvic control 66–67% 76%	Actuarial 5 year overall survival 42% 32%
OUTBACK Trial (RTOG 1174)	2011–2017	Standard cisplatin-based chemo-radiation therapy (108) Standard cisplatin-based chemo-radiation therapy followed by adjuvant chemotherapy (112)	IIIB-IVA	5 year progression free survival 61% 63%	5 year overall survival† 71% 72%

^*Retrospective review from Washington University.

^†Results are for entire cohort, subanalysis by stage not yet published.

Brachytherapy

Brachytherapy, with a shift toward image-guided treatment delivery and an evolution of interstitial applicators, has seen a significant shift in the past decade.³⁴ MRI is now recommended for image-guided adaptive brachytherapy to enable dose optimization and escalation with higher local control rates for large tumors and decreased rates of normal tissue toxicities.^{35 36}

Worldwide, CT imaging continues to be more prevalent in radiation oncology departments. The 2005 French STIC multicentric non-randomized prospective study comparing chemoradiation followed by pulse dose rate brachytherapy using the historic two-dimensional (2D) treatment method to point A versus 3D dosimetric planning via use of CT showed that at 24 months, 3D brachytherapy had improved local control with less toxicity observed than with 2D dosimetry. For patients with advanced tumors (stage IIB–IIIB), local relapse-free survival was 73.9% versus 78.5% with grade 3–4 toxicity of 22.7% versus 2.6% in the 2D and 3D arms, respectively.³⁷ This study showed a benefit to the use of CT, even without utilization of MRI, and highlighted the importance of CT high-risk clinical target volume coverage without increase in normal tissue toxicity.

Retro-EMBRACE, a retrospective study of 731 patients treated with >75% CT-based brachytherapy from 12 centers worldwide showed that 3 year and 5 year pelvic control were 66% and 66% in IIIA, 73% and 67% in IIIB, and 76% and 76% in IVA, respectively. Overall survival at 3 years and 5 years for stage IIIB was 56% and 42%, respectively, and cancer specific survival for IIIB was 65% and 53%. respectively. The actuarial 5-year G3–G5 morbidity for the overall cohort was 5%, 7%, and 5% for bladder, gastrointestinal tract, and vagina, respectively.³⁸ Though progress has been made with brachytherapy, overall survival rates for patients with stage III–IVA disease remain poor. A high enough dose to central disease using a tandem with interstitial needles rather than interstitial needles alone has been shown to predict survival in locally advanced cervical cancer.³⁹ Similarly, in the EMBRACE study, patients treated with more than 85 Gray to the high-risk clinical target volume D90 had better outcomes, highlighting the importance of adequate dose and tumor coverage in outcome optimization for locally advanced cervical cancer.^{40 41} In patients with stage IVA disease, the median minimal dose to 90% of the high risk clinical target volume in equi-effective dose of 2 Gray per fraction of 10 Gray was 86 Gray with a range of 78–89 Gray, resulting in a 5 year local control of 91% with a 95% CI of 75%–97% (Table 2).⁴¹

Table 2.

High-risk clinical target volume, dose, and clinical outcomes for International Federation of Gynecology and Obstetrics 2009 stage III–IVA

International Federation of Gynecology and Obstetrics stage	No of patients	Computed tomography (CT)VHR (cm3)*	Computed tomography (CT)VHR D90% ECD210Gy	Local failure (n)	Pelvic failure (n)	Any failure (n)	Patients who died (n)	5 year local control (95% Cl)	5 year pelvic control (95% Cl)	5 year disease free survival (95% Cl)	5 year overall survival (95% Cl)
IMA	13	30 (24–35)	84 (82–88)	0	0	2	3	100%	100%	76% (43–92)	76% (42–91)
NIB	190	40 (30–56)	88 (83–91)	15	24	61	78	92% (86–95)	86% (79–90)	59% (52–66)	64% (57–71)
IVA	34	57 (39–89)	86 (78–89)	3	6	10	17	91 % (75–97)	81% (62–91)	47% (28–63)	52% (33–68)

Data are numbers, median (IQR), or Kaplan-Meier estimates (95% CI).

Table adapted from Pötter et al⁴¹; EMBRACE Collaborative Group. Lancet Oncol. 2021;22(4):538–547.

^*Mean dose delivered over all fractions.

(CT)VHR, high risk clinical target volume; D_90%, minimal dose to 90% of the clinical target volume; EQD2₁₀Gy, equi-effective dose in 2 Gy per fraction of 10 Gy.

Patients with bladder and rectal involvement require special care during brachytherapy because overdosing these critical structures requires a delicate balance between tumor control and toxicities. Though each case is unique, striving for tumor control is essential if the disease burden is such that brachytherapy dose coverage of sites of tumor including the bladder and rectum is feasible. Unique brachytherapy applicators that cover all sites of disease are preferred (Figure 3). The use of interstitial catheters and very careful optimization minimizing hot-spots but maintaining 100% isodose line coverage is imperative. It may not be feasible to dose reduce tumor to meet organ at risk constraints to standard preferred levels, and side effects must be thoroughly discussed with the patient. Additionally, close follow-up is required for several years to monitor for sequelae.

Figure 3.

Axial and sagittal T2-weighted magnetic resonance imaging during brachytherapy for a patient with stage IVA cervical cancer depicting a tandem and template-based interstitial brachytherapy insertion with interstitial needles that can extend both at a straight and angled trajectory to cover the entire region of disease. In this example, the arrow points to a needle in the bladder at the edge of the tumor. Careful management of hematuria is required when the bladder is intentionally inserted to ensure adequate tumor coverage.

Unfortunately, trends in the USA from 2008 to 2014 demonstrated a decrease in the use of brachytherapy for cervical cancer, and an increase in the use of alternative treatment modalities such as intensity-modulated radiation therapy and stereotactic body radiation therapy for boost, negatively impacting both cancer specific survival and overall survival.⁴² Continued advocacy and education on the vital importance of brachytherapy must be maintained to ensure appropriate life-saving treatment is available for patients.

Follow-up

Three-month follow-up with evaluation of FDG-PET/CT for tumor response has been shown to be a good marker for overall response and prognosis.⁴³ Special care is required for patients with stage III–IVA disease. The presence of hydronephrosis or bladder involvement requires ongoing evaluation and close follow-up by a urologist. For those with a fistula, urology, plastic surgery and general surgery (should colostomy be required), along with gynecologic oncology, form close members of the care team. Pain management is especially pronounced given the proximity to nerve roots and sensitive structures, and early referral to pain management or hospice care is strongly encouraged.

Future Directions

The role of bevacizumab for those with persistent disease or relapsed disease was demonstrated in GOG240.⁴⁴ The roles of bevacizumab or other vascular endothelial growth factor inhibitors, immunotherapy, or other targeted agents are currently being explored in ongoing trials. Whether these agents may benefit patients immediately after chemoradiation, or concurrently, is unknown and may be explored in future trials.

CONCLUSION

The management of stage III–IVA cervical cancer is complex, requiring careful discussion and decision-making with the patient and their family throughout the course of treatment. Engagement of many providers from other disciplines including urology, general surgery, plastic surgery, gynecological oncology, and pain management among others is essential to achieving survival while minimizing morbidity.