This chapter should be cited as follows:
Ohno T, Glob Libr Women's Med
ISSN: 1756-2228; DOI 10.3843/GLOWM.422073

The Continuous Textbook of Women’s Medicine Series – Gynecology Module

Volume 13

Gynecological cancer

Volume Editors: Professor Hextan Ngan, Department of Obstetrics and Gynaecology, The University of Hong Kong, Hong Kong
Professor Karen Chan, Department of Obstetrics and Gynaecology, The University of Hong Kong, Hong Kong

Chapter

Role of Radiotherapy in Cervical Cancer

First published: March 2026

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INTRODUCTION

Radiotherapy has been a cornerstone in the management of cervical cancer, with its well-established role evolving alongside advances in imaging, treatment planning and delivery techniques. When carefully planned and executed, radiotherapy achieves excellent pelvic tumor control and survival outcomes. For selected early-stage tumors, it offers efficacy comparable to that of radical surgery. Radiotherapy remains the primary treatment modality for patients with advanced disease, either alone or in combination with systemic therapies. The integration of concurrent cisplatin-based chemotherapy with radiation has significantly improved local control and survival in patients with locally advanced cervical cancer. Therefore, contemporary indications for radiotherapy span a wide range of disease stages. Optimal treatment selection requires an individualized, multidisciplinary approach that considers clinical, anatomic and social factors, and emphasizes close collaboration among gynecologic oncologists, radiation oncologists and referring physicians.

CLINICAL PRESENTATION

The signs and symptoms of cervical cancer often include abnormal vaginal bleeding, which is the most common early symptom experienced by patients. This abnormal bleeding may manifest during menstrual period, after sexual intercourse or after menopause. Other early symptoms can include offensive vaginal discharge and lower abdominal pain.¹ Many patients do not perceive themselves to be at risk and tend to attribute these initial symptoms to normal bodily changes (e.g. menopause) or common illnesses (e.g. sexually transmitted infections), thus leading to delayed recognition and diagnosis.¹

Additional symptoms that may arise as the disease progresses include heavy vaginal bleeding, which is life-threatening; persistent lower abdominal pain; and symptoms that are severe enough to interfere with daily activities or work routines. Persistent and worsening symptoms despite home-based treatment often prompt patients to seek professional help.¹ Other notable symptoms include abnormal vaginal discharge with a foul odor, pelvic pain and symptoms related to metastasis or effects on other organs in advanced stages.^2,3

Owing to inadequate knowledge of cervical cancer symptoms, particularly in low-resource settings, presentation and diagnosis are often late, thus leading to a more advanced disease at the time of detection.^2,4 Psychological symptoms, such as anxiety and depression, can also be present in patients with cervical cancer and may be influenced by the level of social support and availability of coping resources; however, these symptoms are consequences related to the disease experience rather than the direct symptoms of the cancer itself.^5,6

CLINICAL EVALUATION AND STAGING

Role of imaging in radiotherapy for cervical cancer

Imaging modalities play a crucial role in radiotherapy planning and cervical cancer management by providing the necessary anatomical and functional information for accurate tumor delineation, staging and treatment-response assessment.⁷

Computed tomography (CT) is primarily used to assess extent of disease, particularly lymph node involvement and presence of distant metastases. CT provides essential anatomical detail that aids radiotherapy treatment planning, particularly for dose calculation and targeting. However, its limited soft-tissue contrast restricts its accuracy in evaluating the extent of local tumors.

¹⁸F-fluorodeoxyglucose positron emission tomography with CT (FDG-PET/CT) combines metabolic and anatomical imaging, making it valuable for detecting nodal metastases and distant disease. In advanced disease, PET/CT is particularly useful for radiotherapy planning by identifying the involved lymph nodes and assessing treatment response, which may influence radiotherapy field design and systemic therapy decisions.

Magnetic resonance imaging (MRI) is the preferred modality for local staging of cervical cancer owing to its superior soft-tissue resolution (Figure 1). MRI accurately defines tumor size, parametrial invasion and involvement of adjacent pelvic structures, which is critical for precise radiotherapy planning, including the delineation of gross tumor volume and organs at risk (OARs). This accuracy improves targeting while minimizing damage to the surrounding tissues, particularly in image-guided adaptive brachytherapy.

Ultrasound is used mainly as an initial, accessible tool to evaluate the cervix and pelvic organs and to guide biopsies. It has been suggested as a valid alternative to MRI in the primary diagnostic workup of cervical cancer if performed by an expert sonographer.⁷

For clinical staging, pelvic MRI or transvaginal/transrectal ultrasound enable tumor delineation and the precise assessment of its local extent, including the evaluation of bladder or rectal invasion. Both techniques have very high specificity for confirming involvement of metastatic pelvic lymph nodes. However, their sensitivity is insufficient for detecting small-volume metastases, similar to any currently available imaging modality. Contrast-enhanced CT or FDG-PET/CT are recommended for assessing the spread of extrapelvic tumors.⁷

International Federation of Gynecology and Obstetrics (FIGO) staging system

The FIGO stage is a clinical staging system for classifying gynecologic cancers, including cervical cancer, on the basis of tumor size, local extension and spread to adjacent or distant structures.⁸ It provides a standardized framework for disease assessment and is essential for treatment planning, prognostic evaluation and comparison of clinical outcomes across studies.

Table 1 shows the FIGO 2018 classification. A key update in the FIGO 2018 classification was the incorporation of imaging and pathology results in the FIGO stage. In addition, the size criteria for defining T1b were revised with the introduction of a new subcategory, namely, IB3, thus resulting in the following classifications: IB1 (≤ 2 cm), IB2 (> 2 to ≤ 4 cm) and IB3 (> 4 cm) in the greatest dimension. Furthermore, pelvic lymph node involvement was newly defined as Stage IIIC1, whereas para-aortic lymph node involvement was defined as Stage IIIC2 regardless of the primary tumor size or local extent. As a result, FIGO Stage IIIC disease is highly heterogeneous and associated with variable survival outcomes.⁹

TECHNICAL ASPECTS OF RADIOTHERAPY

Clinical workflow

When a patient is referred, the physician determines the indication for radiotherapy by confirming the patient’s preferences and values and by reviewing the medical history, physical and pelvic examination findings, imaging studies, and other relevant test results, including laboratory findings. In patients with a history of irradiation, the spatial relationship between the previously irradiated area and the requested treatment site should be carefully evaluated. In addition, because comorbidities may increase the risk of adverse events, the following should be confirmed: presence of diabetes mellitus, inflammatory bowel disease, connective tissue disease or renal dysfunction; history of pelvic surgery; and use of anticoagulants or antiplatelet medications.

After informed consent is obtained, immobilization devices are fabricated to ensure reproducibility of patient positioning. A treatment-planning CT scan is performed using the same patient position and pretreatment conditions as those used during irradiation. Thereafter, the CT images are imported into the treatment-planning system, where the beam arrangements are designed for the target tumor and surrounding normal tissues. After the approved treatment plan is verified through measurements and/or calculations, the actual radiation delivery is performed.

External beam radiotherapy (EBRT)

The definitive radiotherapy for cervical cancer requires a combination of EBRT to the pelvis and brachytherapy to the primary cervical tumor.^10,11,12 In patients with FIGO Stage IIIC2 disease, extended-field radiotherapy encompassing the para-aortic region is performed.

The prophylactic irradiation of the para-aortic region is optional in cases with multiple positive pelvic lymph nodes or metastasis to the common iliac lymph nodes; however, there are no randomized controlled trials that strongly support this approach.¹³ By contrast, in early stage cervical cancer, pelvic irradiation that excludes the common iliac lymph nodes may be employed.^13,14 However, determining the target volume according to individual risk factors remains an ongoing challenge.

Whole-pelvic irradiation for cervical cancer using 3D conformal radiotherapy (3D-CRT), intensity-modulated radiotherapy (IMRT) and volumetric-modulated arc therapy (VMAT) involves delivering radiation to the entire pelvic region, including the primary tumor site and regional lymph nodes, to address the potential spread of microscopic disease.

3D conformal radiotherapy (3D-CRT)

In 3D-CRT, radiation beams are shaped on the basis of imaging to conform to the 3D anatomy of the pelvis, allowing targeted dose delivery to the primary tumor site and pelvic lymph node region while sparing some normal tissues. However, 3D-CRT uses static beam arrangements, which may increase radiation delivery to adjacent organs, such as the bladder, rectum and bowels (Figure 2).

Intensity-modulated radiotherapy (IMRT)

IMRT improves upon 3D-CRT by modulating the intensity of individual radiation beams, thus enabling more precise dose sculpting that conforms tightly to the complex pelvic anatomy (Figure 3). This results in better sparing of critical OARs such as the bladder, rectum and small bowel, thus reducing acute and late toxicities. The ability of IMRT to deliver differential doses within the pelvic volume allows the simultaneous integration of boosts to high-risk areas while treating elective nodal regions.

Volumetric-modulated arc therapy (VMAT)

VMAT further advances whole-pelvic irradiation by delivering radiation continuously as the treatment machine rotates around the patient, thus dynamically adjusting the beam shape and intensity in real time. This technique enhances dose conformity and homogeneity across pelvic target volumes and reduces treatment time compared with static IMRT. VMAT maintains or improves OAR sparing, contributes to lower toxicity profiles and improves patient comfort during treatment.

Stereotactic body radiotherapy (SBRT)

SBRT is a highly precise form of radiotherapy that delivers large doses in few fractions to limited metastatic sites, with minimal damage to the surrounding tissues. SBRT is increasingly being used in gynecological oncology, including cervical cancer, for treating oligometastatic diseases or in patients unsuitable for brachytherapy. It offers good local control and is favorable for patients who are not candidates for intracavitary brachytherapy. SBRT is generally considered when definitive local control of limited metastases is desired or as a boost in patients ineligible for brachytherapy. The recommended SBRT dose for cervical cancer boost has been evaluated in clinical studies, with doses of 22.5 Gy delivered in three fractions showing acceptable toxicity profiles.¹⁵

Particle beam therapy

Proton and carbon ion radiotherapy for gynecological malignancies, including cervical cancer, utilizes charged particles that deliver radiation with distinct physical and biological properties compared with conventional X-rays. These particles exhibit a characteristic Bragg peak, allowing for maximal energy deposition at a specific depth with a minimal exit dose beyond the target. Carbon ion radiotherapy offers additional potential advantages because of its higher linear energy transfer, resulting in increased relative biological effectiveness.¹⁶ This can enhance tumor cell kill, particularly in photon-resistant tumors such as adenocarcinoma, malignant melanoma and hypoxic tumors, thus potentially improving local control.^17,18

Image-guided brachytherapy

Intracavitary brachytherapy is an essential component in definitive radiotherapy for cervical cancer in FIGO 2018 clinical Stages IA2–IVA. Except in cases in which brachytherapy cannot be performed because of patient- or tumor-related factors, the use of highly conformal external beam radiation techniques, such as IMRT or SBRT, as substitutes for brachytherapy is not recommended.

Brachytherapy for cervical cancer has evolved from conventional treatment planning based on prescription to point A using orthogonal radiographs to 3D image-guided brachytherapy (3D-IGBT), which employs imaging modalities, such as CT and MRI, acquired with the applicator in place (Figure 4). In 3D-IGBT, target volumes and OARs are delineated on 3D images, and dose prescription and evaluation are performed on the basis of dose distribution and dose–volume histogram parameters.¹⁹ A major advantage of 3D-IGBT is the ability to develop treatment plans while visualizing the target organs, including the uterus, bladder and rectum, thereby enabling greater individualization of treatment.

More recently, hybrid brachytherapy, which is also referred to as combined intracavitary and interstitial brachytherapy, has been developed to improve dose distribution by adding a limited number of interstitial needles to intracavitary brachytherapy (Figure 4).²⁰ Hybrid brachytherapy is particularly indicated when adequate dose coverage of the high-risk clinical target volume cannot be achieved with intracavitary brachytherapy alone or when compliance with dose constraints for adjacent OARs is difficult.

Advances in brachytherapy techniques have led to improved local control of cervical tumors (90–95% with CT- or MRI-guided brachytherapy) without increasing the incidence of severe adverse events.^21,22 Table 2 summarizes the clinical outcomes of MRI-guided brachytherapy for cervical cancer. At the same time, these advances require a higher level of technical expertise and careful attention to medical safety from clinical staff. In addition to cervical cancer, 3D-IGBT can be applied to other gynecological malignancies requiring brachytherapy, such as endometrial and vaginal cancers.

Overall treatment time (OTT) considerations

Prolonged OTT after radiotherapy for cervical cancer is consistently associated with poor survival outcomes, including reduced overall survival (OS), disease-free survival (DFS) and local tumor control. This negative effect is mainly attributed to accelerated tumor cell repopulation during treatment delays or interruptions, which diminishes the effectiveness of radiotherapy.^23,24 Clinical evidence shows that shorter, uninterrupted treatment courses lead to better survival and local control, whereas OTT prolongation increases the risk of recurrence and treatment failure. Maintaining an OTT of approximately 7 weeks or less during radiotherapy for cervical cancer is recommended to maximize efficacy.¹¹

In resource-limited settings, delays before and during radiotherapy often result in more advanced disease at treatment initiation, thus further worsening prognosis ('stage migration').²⁵ Overall, there is a clear inverse relationship between OTT duration and survival in cervical cancer, underscoring the importance of timely, continuous radiotherapy (preferably combined with chemotherapy) to optimize patient outcomes.

ROLE OF CHEMOTHERAPY/IMMUNOTHERAPY IN COMBINATION WITH RADIOTHERAPY

Concurrent chemoradiotherapy (CCRT)

In 1999, the USA National Cancer Institute issued a significant clinical alert recommending CCRT with cisplatin-based chemotherapy and radiation as the new standard of care for locally advanced cervical cancer, replacing radiation alone, based on compelling trial results showing improved survival.²⁶ Since then, CCRT for cervical cancer has been widely adopted worldwide as a standard treatment. The chemotherapy regimen most commonly used for CCRT is single-agent cisplatin administered at a dose of 40 mg/m² weekly. To date, cisplatin-based combination chemotherapy has not been shown to be superior to single-agent cisplatin in this setting. As shown in Table 3, clinical trials have demonstrated that CCRT improves intrapelvic tumor control.²⁷ In contrast, the reduction in distant metastases likely reflects not only the direct antitumor effects of chemotherapy but also a secondary effect resulting from improved local control and reduced local recurrence. Notably, the response rate to single-agent cisplatin in cervical cancer is limited to approximately 20–30%, and its curative potential when used alone is modest.

According to a meta-analysis by Green et al. comparing CCRT with radiotherapy, CCRT significantly reduced both local and distant recurrence and resulted in significant improvements in OS and DFS.²⁸ The benefit in 5-year survival was 8% overall for patients with Stages IB–IIA disease (hazard ratio (HR), 0.78). However, when analyzed by stage, the survival benefit decreased with advancing disease stage: 10% for Stages IB–IIA, 7% for Stage IIB and 3% for Stages III–IVA.²⁹ Nevertheless, even in patients with Stage IIIB cervical squamous cell carcinoma, a more recent report shows that CCRT provides a significant survival advantage compared with radiotherapy alone.³⁰

With regard to toxicity, the above meta-analysis demonstrated that CCRT was associated with a 3.6-fold increase in Grades-3–4 hematologic toxicity, including a 2.2-fold increase in leukopenia and a 2.4-fold increase in thrombocytopenia, as well as a 2.0-fold increase in Grades-3–4 acute gastrointestinal toxicity.²⁸ By contrast, no significant increase in Grades-3–4 acute toxicity was observed in the urinary tract or skin.

Subsequent clinical trials focused on the development of new combination therapies based on an established CCRT framework. The representative clinical trials are described below.

Induction chemotherapy followed by CCRT

The INTERLACE trial was a Phase-III randomized study that compared CCRT alone with induction chemotherapy followed by CCRT in patients with locally advanced cervical cancer.³¹ Patients in the experimental arm received weekly carboplatin and paclitaxel for six cycles prior to standard CCRT.

Among the 500 enrolled patients, the majority had Stage-II disease and negative lymph node status. At a median follow-up of 64 months, induction chemotherapy followed by CCRT was associated with improved 5-year DFS and OS compared with CCRT alone.

However, the details of the radiotherapy component are limited. IMRT and 3D-IGBT were used in a subset of patients, and the prescribed dose to point A (equivalent dose in 2-Gy fractions [EQD2] of ≥ 78 Gy) was lower than that reported in contemporary studies, such as EMBRACE. Although treatment completion rates were high, a careful interpretation of the results is warranted owing to the incomplete reporting and potential variability in the radiotherapy dose and technique.

CCRT and adjuvant chemotherapy

The OUTBACK trial was a multicenter, randomized Phase-III study in which adults with locally advanced cervical cancer were assigned to receive standard cisplatin-based CCRT alone or the same CCRT followed by adjuvant carboplatin and paclitaxel.³² The trial evaluated whether four cycles of adjuvant chemotherapy administered after definitive CCRT could improve survival compared with CCRT alone. Radiotherapy consisted of 45.0–50.4 Gy of pelvic external beam irradiation with weekly cisplatin, followed by intracavitary brachytherapy according to standard practice. After a median follow-up of 5 years, adjuvant chemotherapy did not improve OS (72% vs 71%; HR, 0.90), and no benefit in disease progression or survival was observed. By contrast, adjuvant chemotherapy was associated with increased hematologic toxicity and serious adverse events, thus suggesting that the routine use of adjuvant carboplatin and paclitaxel after CCRT is not beneficial in unselected patients with locally advanced cervical cancer.

Immunotherapy and CCRT

In the CALLA randomized, double-blind Phase-3 trial, adults with previously untreated, locally advanced cervical cancer (FIGO 2009 Stages IB2–IIB with nodal involvement or Stages III–IVA) were assigned to receive standard CCRT with or without the programmed death-ligand 1 antibody durvalumab.³³ Radiotherapy consisted of 45 Gy EBRT delivered in 25 fractions with weekly cisplatin or carboplatin, followed by image-guided brachytherapy using high-dose-rate or low-/pulse-dose-rate techniques to deliver a total dose of 27.5–30 Gy or 35–40 Gy, respectively. After a median follow-up of approximately 18 months, progression-free survival (PFS) did not differ significantly between the groups (HR, 0.84), although treatment was generally well tolerated with comparable rates of Grade-3–4 toxicities. These findings indicate that the addition of durvalumab to CCRT did not improve PFS.

The KEYNOTE-A18 trial was a Phase-III randomized study evaluating the addition of pembrolizumab to CCRT in patients with cervical cancer.³⁴ This trial enrolled patients with FIGO 2014 Stages IB2–IIB with positive lymph node status and those with Stages III–IVA and conducted a comparison between CCRT alone and CCRT combined with pembrolizumab. In the experimental arm, pembrolizumab was administered concurrently with CCRT at a dose of 200 mg every 3 weeks for five cycles, followed by maintenance therapy with pembrolizumab at 400 mg every 6 weeks for up to 15 cycles. At a median follow-up of 17.9 months, the 2-year PFS was 57.3% in the CCRT-alone group (n = 531) and 67.8% in the pembrolizumab plus CCRT group (n = 529), thus demonstrating that a statistically significant improvement was achieved with the addition of pembrolizumab (HR = 0.70; P = 0.002). The incidence of Grade ≥ 3 diarrhea was 4% in both treatment groups. Highly conformal external beam radiation techniques, such as IMRT and VMAT, were used in nearly 90% of the patients. The total combined dose from EBRT and brachytherapy reached approximately 87 Gy EQD2 in both treatment arms, indicating that high-quality radiotherapy was delivered.

COMPLICATIONS OF RADIOTHERAPY

Adverse events

Adverse events caused by radiotherapy are generally classified into acute adverse events and late adverse events. Acute adverse events occur within 90 days of the start of treatment, whereas late adverse events occur at 91 days or later. Acute reactions are primarily caused by inflammation and are often reversible. By contrast, late reactions are mainly due to fibrosis (overgrowth of connective tissue) and thickening of the vascular intima, which leads to impaired blood flow. These changes are typically difficult to reverse and often become chronic.

Bone marrow

Lymphocytes, a type of white blood cell, are highly sensitive to radiation. When a large area such as the entire pelvis is irradiated, lymphocyte counts decrease early during treatment. The combination of whole-pelvic irradiation with concurrent chemotherapy and/or para-aortic irradiation increases the risk of leukopenia. A recent systematic review reported a significant increase in hematologic toxicity for whole-pelvic-bone doses of V10Gy > 95–75%, V20Gy > 80–65% and V40Gy > 37–28%.³⁵

Skin

Acute skin reactions usually appear 2–3 weeks after the start of radiotherapy and include dryness, redness (erythema) and pigmentation in the irradiated area. If the damage reaches the dermis, moist desquamation with fluid discharge may occur. Skin reactions tend to be more severe when the radiation field includes the perineal region owing to lower vaginal extension or when it includes areas such as the intergluteal cleft and anal region.

Maintaining the cleanliness of the affected skin is essential. Heparinoid-containing moisturizers are commonly used to treat dryness, and dimethyl isopropylazulene ointment may be applied for inflammation. Topical corticosteroids are administered when itching or redness is severe. Physical irritation, such as friction, and chemotherapy use are risk factors for worsening skin reactions.

Late skin effects include hyperpigmentation, hypopigmentation, telangiectasia (small blood vessels) and skin atrophy.

Nausea and vomiting

According to the MASCC/ESMO 2023 guidelines, the risk of nausea and vomiting during pelvic radiotherapy is classified as low risk, whereas irradiation involving to the upper abdomen is considered moderate risk.³⁶ For prevention and treatment, 5-HT3 receptor antagonists, dexamethasone and dopamine antagonists are recommended.

The concurrent administration of chemotherapy increases the risk of nausea and vomiting, and antiemetic therapy should be selected on the basis of the chemotherapy risk classification. For patients with cervical cancer receiving concurrent weekly cisplatin and radiotherapy, a three-drug combination (5-HT3 receptor antagonists, dexamethasone, and aprepitant/fosaprepitant) is recommended.

Gastrointestinal tract

During pelvic radiotherapy, diarrhea is a common acute adverse event that usually improves after treatment completion. Probiotics and intestinal regulators are used for basic treatment, and loperamide hydrochloride is added when necessary.³⁷

Late adverse events include radiation proctitis (urgency and rectal bleeding), small bowel injuries such as intestinal obstruction, and rectovaginal fistula, each occurring in less than 5% of patients.

During endoscopic examination for rectal bleeding, biopsy of the irradiated area should be avoided unless a new tumor is suspected because biopsy may increase the risk of bowel perforation in the irradiated tissue. A history of abdominal or pelvic surgery increases the risk of bowel obstruction, whereas the use of anticoagulants or antiplatelet agents increases the risk of bleeding. In cases with rectal bleeding, constipation should be avoided. Mild bleeding often improves with conservative treatment involving carbazochrome sodium sulfonate or tranexamic acid.

If bleeding is severe or persistent, endoscopic therapy (argon plasma coagulation), hyperbaric oxygen therapy or surgery is required.

Bladder

Radiation cystitis is caused by damage to the bladder mucosa, similar to radiation proctitis. The acute symptoms include frequent urination, pain during urination and incomplete bladder emptying. Medications are commonly used for an overactive bladder, and antibiotics are prescribed when an infection is present.

Late adverse events include reduced bladder capacity due to fibrosis, ureteral strictures and vesicovaginal fistulas (> 5%). Hematuria (blood in the urine) may occur more than 5 years after treatment.³⁸ Most cases respond to conservative treatment; however, severe hemorrhagic cystitis may require total cystectomy. Hyperbaric oxygen therapy has also been demonstrated to be effective.

Ovaries

Oocytes (egg cells) are highly sensitive to radiation exposure. Ovarian failure typically occurs when curative doses are administered to the pelvis. In young patients, menopausal symptoms may appear early, and fertility cannot be preserved.

Vagina

Vaginal stenosis and sexual dysfunction represent ongoing clinical challenges following radiotherapy. Incremental radiation doses have been associated with a higher incidence of vaginal stenosis, and 45–50% of patients experience vaginal stenosis at approximately 45 Gy.³⁹ Vaginal dilatation therapy is widely recommended to prevent radiation-induced vaginal stenosis, and higher adherence is associated with a lower prevalence of this complication. However, patient adherence remains limited owing to the discomfort, lack of personalization and physical rigidity of the current dilators.³⁹

Bones

Late bone complications after pelvic radiotherapy include insufficiency fractures, which occur in approximately 14% of patients undergoing irradiation.⁴⁰ A meta-analysis showed that, among cases with pelvic insufficiency fractures, the proportion of symptomatic patients was 61%. IMRT was associated with a significantly lower fracture rate. Insufficiency fractures most commonly occurred in the sacrum (40%), followed by the pubis (13%) and lumbar vertebrae (7%). The median time to fracture was 7.1–19 months after radiotherapy.⁴⁰ Risk factors identified in another meta-analysis included postmenopausal status, osteoporosis and diabetes mellitus.⁴¹

Secondary cancer

Secondary cancer after radiotherapy refers to any new cancer that develops after treatment. After radiotherapy for cervical cancer, the relative risk of secondary cancer is approximately 1.2–1.3 times that of the general population overall.^42,43 Compared with the general population, risks for HPV-related cancers (pharynx, genital sites and rectum/anus) and smoking-related cancers (pharynx, trachea/bronchus/lung, pancreas and urinary bladder) were elevated in both radiotherapy and non-radiotherapy groups. Additionally, cervical cancer patients receiving radiotherapy were at an increased risk for cancers at heavily irradiated sites (colon, rectum/anus, urinary bladder, ovary and genital sites) compared with the general population.⁴² However, the long-term survival benefits of radiotherapy outweigh these risks.

MANAGEMENT OF ANEMIA

Etiology of anemia

Patients with cervical cancer frequently present with anemia, which can arise from multiple factors. Tumor-related bleeding, particularly genital bleeding, tends to worsen as the disease progresses, thus resulting in more severe anemia in the advanced stages. In addition, comorbid conditions (e.g. chronic inflammation and infection) and anticancer treatments (e.g. radiotherapy and cisplatin-based chemotherapy) may contribute to the development of anemia.

Prognostic effect

Anemia has long been reported as a poor prognostic factor after definitive radiotherapy for cervical cancer. One proposed explanation is that anemia leads to tumor hypoxia, which results in increased radioresistance. However, the correction of anemia does not necessarily translate into improved clinical outcomes, and the underlying biological mechanisms affecting radiation response remain incompletely understood.

Treatment-related anemia and bone marrow toxicity

With regard to treatment-related effects on anemia, attention should be paid to bone marrow suppression associated with pelvic EBRT and combined chemotherapy as well as bleeding related to applicator insertion during brachytherapy. Miszczyk et al. reported the results of a meta-analysis evaluating the effect of bone marrow-sparing radiotherapy on hematologic toxicity.⁴⁴ EBRT delivered with highly conformal techniques, such as IMRT or VMAT, resulted in significant reductions in grade ≥ 3 leukopenia and grade ≥ 2 neutropenia. However, no significant reduction in the incidence of anemia or thrombocytopenia was observed.

Red blood cell transfusion

Clear criteria for red blood cell transfusion in patients with anemia and cervical cancer undergoing radiotherapy have not yet been established. Zayed et al. conducted a systematic review addressing this issue and reported wide variability in transfusion thresholds, with hemoglobin levels of 8 to 12 g/dL.⁴⁵ Regarding oncologic outcomes, six studies found that there were no survival benefits associated with red blood cell transfusion, whereas three studies suggested a potential improvement.

Evidence from head and neck cancer

Anemia has also been reported as a poor prognostic factor for head and neck cancer. Hoff et al. performed a pooled analysis of the DAHANCA 5 and DAHANCA 7 trials, in which patients with low pretreatment hemoglobin levels (women < 13.0 g/dL, men < 14.5 g/dL) were randomized to receive or not receive red blood cell transfusion.⁴⁶ Regardless of transfusion status, patients with low hemoglobin levels had worse local control, disease-specific survival and OS, and no prognostic benefit from transfusion was observed.

Overall, there is currently no clear evidence that red blood cell transfusion improves oncological outcomes in patients with anemia undergoing radiotherapy.

POSTOPERATIVE RADIOTHERAPY

Indications for adjuvant radiotherapy

In cervical cancer, the decision to administer adjuvant therapy (treatment after surgery) is based on the pathological findings from the hysterectomy and lymphadenectomy. Careful patient selection and multidisciplinary coordination are essential to balance therapeutic benefits against potential complications and ensure an improved quality of life after treatment. These patients were categorized into high- and intermediate-risk groups.

Postoperative radiotherapy (PORT) concurrent with cisplatin-based chemotherapy after hysterectomy for cervical cancer is indicated primarily in patients with high-risk pathological features, such as positive surgical margins, lymph node involvement, and parametrial invasion.⁴⁷ These factors are associated with an increased likelihood of residual microscopic disease and local recurrence. PORT aims to eradicate residual disease, thereby improving local control and potentially enhancing long-term survival outcomes. Adding chemotherapy to PORT appeared to provide a smaller absolute benefit when only one node is positive or when the tumor size is < 2 cm.⁴⁸

If the surgical margins and lymph nodes are negative but the tumor has aggressive local features, the patient is classified as intermediate risk.⁴⁹ These features may include deep stromal invasion, lymphovascular space invasion and large tumor size. Adjuvant radiotherapy or CCRT has been used for intermediate-risk patients. In the GOG263/KGOG1008 study, although recurrence-free survival and OS favored CCRT, the addition of weekly cisplatin during radiotherapy did not result in a statistically significant improvement in the intermediate-risk group.⁵⁰ CCRT increased Grade-3 and -4 adverse events with a transient decline in quality of life.

Advances in PORT

The severe adverse events associated with PORT for cervical cancer include bowel obstruction and ureteral strictures resulting from tissue fibrosis. Furthermore, treatment often leads to lower-extremity lymphedema, which may worsen recurrent cellulitis. Radiation techniques used in postoperative settings have evolved, particularly with the availability of IMRT and 3D-CRT. In cervical cancer, IMRT has shown equivalent clinical outcomes (pelvic recurrence-free survival and DFS) to those of 3D-CRT but with significantly reduced gastrointestinal and genitourinary toxicities, thus improving the therapeutic ratio.^51,52 In addition, patient-reported sexual function was similar between the treatment groups. After radiotherapy, fear of sex decreased and interest in sex improved over time.⁵³

TREATMENT OF RECURRENT AND METASTATIC DISEASE

Pelvic recurrence

The management of recurrent gynecological cancer requires the centralization of care within experienced centers and the close collaboration of a multidisciplinary team, with an emphasis on individualized decision making, patient counseling, clinical trial participation and early palliative care integration. The diagnostic workup aims to define the extent of locoregional and metastatic disease, preferably with histologic confirmation, and to distinguish patients suitable for radical, potentially curative treatment, particularly those with oligorecurrent disease, from those with multifocal or widely metastatic disease for whom radical approaches are inappropriate. Prognostic factors must be carefully weighed against the risk of major treatment-related morbidities.

According to the guidelines of the European Society of Gynaecological Oncology, European Society for Radiotherapy and Oncology, and European Society of Pathology,¹¹ definitive chemoradiotherapy with IGBT is the treatment of choice for central recurrence after primary surgery in radiotherapy-naïve patients. Pelvic sidewall recurrence may be managed with definitive chemoradiotherapy in radiotherapy-naïve patients, whereas extended pelvic surgery aimed at complete resection may be considered when radical radiotherapy is not feasible. In patients previously treated with radiotherapy, pelvic exenteration is recommended for selected central recurrences without sidewall or extrapelvic involvement, whereas re-irradiation with IGBT or extended surgery may be considered in selected cases at specialized centers. Patients who are not candidates for radical local treatment should receive systemic chemotherapy with additional therapies guided by treatment response.

Distant metastatic disease

Palliative radiotherapy is typically used to relieve symptoms, such as pain, bleeding or obstruction caused by primary tumors or metastatic sites. Specifically, it is used to relieve pain due to bone metastases or soft-tissue invasion by tumors, neurological deficits resulting from brain metastases or spinal cord compression due to bone metastases, obstructive or stenotic symptoms involving the airway or esophagus, and tumor-related exudation or bleeding. Palliative radiotherapy aims to maintain or improve a patient’s quality of life.

The standard of care for Stage-IVB cervical cancer primarily involves systemic therapy, including cytotoxic chemotherapy, anti-angiogenic therapy and immunotherapy. Radiotherapy in Stage-IVB cervical cancer plays a palliative role and, in selected cases, may have a curative role depending on the disease burden and patient factors.

Several retrospective studies demonstrated that the use of definitive pelvic radiotherapy in patients with Stage-IVB cervical cancer was associated with better oncologic outcomes, such as PFS, cause-specific survival and OS.^54,55 In addition, Li et al. reported that 60 patients who received curative-intent irradiation for primary and metastatic sites showed a 5-year OS rate of 51% and a 5-year PFS of 26%. In their study, lymphatic metastases had a better OS than hematogenous metastases, and patients with one metastasis site showed a more favorable prognosis than patients with ≥ 2 metastases sites.⁵⁶ The prospective evaluation of systemic treatment with or without definitive pelvic radiotherapy is highly warranted to identify patients who benefit from the radiotherapy.

SBRT can be considered for patients with cervical cancer who develop synchronous or metachronous oligometastatic disease. In a cohort of 215 patients with gynecologic oligometastases, SBRT achieved excellent local control, with a 5-year local recurrence rate of only 18.5%, despite a high 5-year distant recurrence rate of 73.1%. Notably, the treatment provided a 5-year OS of 33.1% and a median chemotherapy-free survival of 21.7 months, thus highlighting the role of SBRT in delaying systemic therapy and maintaining quality of life.⁵⁷

PRACTICE RECOMMENDATIONS

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