# Cervical Cancer: Concurrent Chemoradiation and Brachytherapy

## Introduction

Cervical cancer remains one of the most common malignancies worldwide, and radiation therapy plays a central curative role in its management. For patients with locally advanced cervical cancer, defined as FIGO stage IB3 to IVA, the standard treatment approach is concurrent cisplatin-based chemoradiation followed by brachytherapy. This combined modality was established by five landmark trials conducted by the Gynecologic Oncology Group (GOG) and the National Cancer Institute (NCI) in 1999, and it remains one of the most robust evidence-based treatment paradigms in radiation oncology. Brachytherapy is an essential and non-omissible component of this regimen; omitting brachytherapy is associated with significantly worse survival outcomes.

## Staging

### FIGO 2018 Staging Updates

The 2018 revision of the FIGO staging system for cervical cancer incorporates imaging and pathologic findings, moving beyond the previous clinical-only staging approach. Notably, stage IIIC1 designates pelvic lymph node involvement detected by imaging or pathology, while stage IIIC2 indicates para-aortic lymph node involvement. Magnetic resonance imaging (MRI) of the pelvis is the preferred modality for assessing local tumor extent, whereas positron emission tomography/computed tomography (PET/CT) is recommended for evaluating nodal and distant metastases.

### Workup

The diagnostic workup for locally advanced cervical cancer includes a thorough pelvic examination under anesthesia to assess tumor extent. MRI of the pelvis is utilized to delineate the local tumor, assess parametrial invasion, and measure tumor dimensions accurately. PET/CT scans are employed to evaluate nodal involvement and detect distant metastases. Laboratory studies such as complete blood count and renal function tests are necessary to determine eligibility for cisplatin chemotherapy. If bladder or rectal involvement is suspected, cystoscopy and proctoscopy should be considered to assess mucosal invasion.

## The Evidence for Concurrent Chemoradiation

### NCI Alert (1999)

In 1999, the NCI issued an alert based on five randomized trials—GOG 85, GOG 120, GOG 123, RTOG 9001, and SWOG 8797—that demonstrated a significant survival benefit when concurrent cisplatin-based chemotherapy was added to radiation therapy. These studies showed a 30-50% reduction in the risk of death compared to radiation alone, thereby establishing concurrent chemoradiation as the standard of care for stage IB2 to IVA cervical cancer.

### Key Trial: GOG 120

The GOG 120 trial compared three different chemoradiation regimens for locally advanced cervical cancer. Weekly cisplatin at a dose of 40 mg/m² emerged as the simplest regimen with equivalent efficacy to more complex schedules. This trial established weekly cisplatin as the standard concurrent chemotherapy regimen.

### Key Trial: RTOG 9001

The RTOG 9001 trial compared pelvic radiation therapy combined with concurrent cisplatin and 5-fluorouracil (5-FU) chemotherapy versus pelvic and para-aortic radiation therapy alone. The chemoradiation arm demonstrated improved overall survival and disease-free survival, with an 8-year overall survival rate of 67% compared to 41% in the radiation-only group.

## Treatment Components

### External Beam Radiation Therapy (EBRT)

#### Target Volumes

The primary tumor volume, including the gross tumor volume (GTV) and clinical target volume (CTV), encompasses the cervix, uterus, parametria, and upper vagina, as defined by MRI imaging. The nodal CTV includes the common iliac, external iliac, internal iliac, obturator, and presacral lymph nodes. If imaging reveals para-aortic nodal involvement, the radiation field is extended to cover the para-aortic nodes up to the T12-L1 vertebral level.

#### Dose

The standard EBRT dose to the elective pelvic volume is 45 Gy delivered in 25 fractions. Involved lymph nodes may receive a simultaneous integrated boost (SIB) or a sequential boost to a total dose of 55-60 Gy. When indicated, extended-field para-aortic radiation therapy is delivered to 45 Gy.

#### Technique

Intensity-modulated radiation therapy (IMRT) has become the standard technique for EBRT in cervical cancer due to its ability to reduce bowel and bone marrow toxicity. Daily image-guided radiation therapy (IGRT) is recommended to ensure accurate treatment delivery. The RTOG 1203 (TIME-C) trial demonstrated that IMRT significantly reduces gastrointestinal and genitourinary toxicity compared to conventional four-field techniques.

![IMRT plan for locally advanced cervical cancer showing pelvic nodal and parametrial coverage](images/cervical-imrt-plan.jpg)

### Concurrent Chemotherapy

Concurrent chemotherapy consists of weekly cisplatin at 40 mg/m² administered for 5 to 6 cycles during EBRT. Pre-hydration and anti-emetic medications are required to manage cisplatin-related toxicities. For patients who are ineligible for cisplatin due to renal insufficiency, weekly carboplatin dosed at an area under the curve (AUC) of 2 is an acceptable alternative. It is important to maintain adequate blood counts to minimize treatment interruptions.

### Brachytherapy

#### Importance

Brachytherapy is a non-negotiable component of curative treatment for cervical cancer. Its omission results in a 10-15% absolute reduction in overall survival. Brachytherapy delivers a very high radiation dose directly to the cervix while sparing surrounding normal tissues due to rapid dose fall-off. It typically begins during or shortly after EBRT, ideally starting by the fifth week of treatment.

#### Intracavitary Technique

The intracavitary brachytherapy applicators commonly used include tandem and ovoids (Fletcher-Suit), tandem and ring (Vienna style), and tandem and cylinder. These applicators are inserted under sedation or general anesthesia. MRI-based treatment planning is preferred, following the EMBRACE paradigm, to optimize dose distribution and target coverage.

#### Dose and Fractionation (HDR)

High-dose-rate (HDR) brachytherapy is commonly delivered in 5 to 6 fractions of 5 to 6 Gy each to the high-risk clinical target volume (HR-CTV). The goal is to achieve a cumulative equivalent dose in 2 Gy fractions (EQD2) of 85-90 Gy when combined with EBRT. Fractions may be administered once or twice weekly.

#### Dose Constraints (EQD2)

Dose constraints to minimize toxicity include limiting the bladder D2cc to less than 80 Gy, rectum D2cc to 65-75 Gy, sigmoid colon D2cc to 70-75 Gy, and bowel D2cc to less than 75 Gy.

| Structure | Constraint (EQD2, α/β = 3 Gy) | Toxicity Endpoint |
|---|---|---|
| HR-CTV D90 | ≥ 85–90 Gy (combined EBRT + brachy) | Local control target |
| Bladder D2cc | < 80 Gy | Fistula, cystitis |
| Rectum D2cc | < 65–75 Gy | Proctitis, fistula |
| Sigmoid D2cc | < 70–75 Gy | Perforation, stricture |
| Bowel D2cc | < 75 Gy | Perforation, obstruction |

![Tandem and ovoid applicator in situ with isodose distribution for cervical brachytherapy](images/cervical-brachy-applicator.jpg)

## Treatment Timeline

The overall treatment time, combining EBRT and brachytherapy, should not exceed 7 to 8 weeks. Prolongation beyond 8 weeks is associated with inferior local control and survival outcomes, with an estimated loss of approximately 1% local control for each day of treatment delay. Brachytherapy should commence no later than weeks 5 to 6 of treatment and be completed concurrently with or shortly after EBRT.

## Emerging Agents

The KEYNOTE-A18 (ENGOT-cx11) trial evaluated the addition of pembrolizumab, an immune checkpoint inhibitor, to concurrent chemoradiation versus chemoradiation plus placebo. This study demonstrated improved progression-free survival with pembrolizumab and led to FDA approval of pembrolizumab combined with chemoradiation for FIGO 2014 stage III to IVA cervical cancer. This represents the first modification to the standard chemoradiation backbone in over 25 years.

## Outcomes

Five-year overall survival rates vary by stage: 65-80% for stage IB-II, 40-60% for stage III, and 15-30% for stage IVA disease. Local control rates with complete chemoradiation and brachytherapy exceed 85-90% for early-stage disease and 70-80% for locally advanced disease.

![Survival curves comparing chemoradiation with radiation alone for locally advanced cervical cancer](images/cervical-chemorad-survival.jpg)

## Key Clinical Pearls

Concurrent weekly cisplatin at 40 mg/m² combined with pelvic radiation remains the standard of care for locally advanced cervical cancer, reducing mortality by 30-50% compared to radiation alone. Brachytherapy is an indispensable component of treatment; omitting it results in a 10-15% absolute decrease in overall survival. The total treatment duration should not exceed 7 to 8 weeks, as each day of prolongation reduces local control by approximately 1%. The addition of pembrolizumab to chemoradiation, as demonstrated in the KEYNOTE-A18 trial, has shown a progression-free survival benefit for stage III to IVA disease and marks the first new addition to the standard regimen in over two decades.

## References

1. Rose PG, Bundy BN, Watkins EB, et al. Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer. *N Engl J Med*. 1999;340(15):1144-1153.  
2. Eifel PJ, Winter K, Morris M, et al. Pelvic irradiation with concurrent chemotherapy versus pelvic and para-aortic irradiation for high-risk cervical cancer: an update of RTOG 90-01. *J Clin Oncol*. 2004;22(5):872-880.  
3. Lorusso D, Xiang Y, Hasegawa K, et al. Pembrolizumab plus chemoradiotherapy for high-risk locally advanced cervical cancer: a randomized, double-blind, phase 3 ENGOT-cx11/GOG-3047/KEYNOTE-A18 trial. *J Clin Oncol*. 2024;42(10):1145-1155.  
4. Han K, Milosevic M, Fyles A, et al. Trends in the utilization of brachytherapy in cervical cancer in the United States. *Int J Radiat Oncol Biol Phys*. 2013;87(1):111-119.