A total of 181 patients (mean age, 56.3 years; range, 27–83) with cervical squamous-cell cancer who were treated with IMRT and high-dose-rate brachytherapy (HDR BT) at the Sun Yat-Sen University Cancer Center (Guangzhou, China) between March 2011 and May 2013 were retrospectively reviewed. Among them, 74 patients were excluded for meeting any one of the following criteria: i) Stage IVB disease; ii) distant nodal metastasis in inguinal, mediastinal or supraclavicular lymphatics; iii) treatment with salvage, palliative or adjuvant intent; or iv) incomplete radiotherapy due to patient refusal or poor performance status. The Institutional Review Board of the Sun Yat-Sen University Cancer Center approved the present study.

Among the remaining patients, 55 and 52 patients were treated with EF-IMRT and pelvic IMRT, respectively. All patients underwent abdominal and pelvic magnetic resonance imaging (MRI) to assess nodal metastasis and tumor size. As a result of economic factors, the majority of patients underwent a chest X-ray and color ultrasound of the supraclavicular region to evaluate the distant metastasis instead of a positron emission tomography (PET) and chest computed tomography (CT) scan. The patient characteristics of the two groups are presented (Table I).

All patients were treated with a combination of IMRT and HDR BT. The IMRT process incorporated CT-based simulation, performed with a full bladder and an empty rectum, and each patient underwent a planning CT scan from the upper border of T10 to the ischialtuberosity, with a 3-mm slice thickness (Philips Medical Systems, Inc., Bothell, WA, USA). The target volumes and organs at risk, including the spinal cord, bowel, kidneys, bladder, rectum and femoral heads, were drawn on each planning CT slice (5). Involved lymph nodes (a short-axis diameter on CT/MRI of >1 cm) were contoured as gross tumor volume (GTV-N). The cervical tumor and uterus were contoured as high-risk CTV (HR-CTV), and the doses were increased in BT, but not in external-beam radiotherapy.

The clinical target volume (CTV) included all areas of gross and potentially microscopic diseases. The pelvic CTV consisted of a 0.7 to 2-cm margin around the vessels, cervix, uterus, parametria, presacral space and vagina (6). The inguinal region was drawn as part of the CTV when the distal vagina or inguinal lymph nodes was considered to be involved, according to imaging and clinical examination.

Patients with evidence for positive involvement of para-aortic or high common iliac nodes were treated with EFR to the superior border of the first lumbar vertebra. The CTV in the para-aortic region was contiguous with the pelvic lymph node stations and encompassed the aorta and inferior vena cava with a 1- to 1.5-cm minimum margin (7).

The GTV-N was expanded by 0.5 cm to create the planning target volume of the GTV-N (PTVGTV-N) and the CTV was expanded by 0.6–1 cm to create the PTVCTV, accounting for patient motion and set-up uncertainty. The CTV dose was 45 Gy in 25 fractions, with a concomitant boost of GTV-N to a dose of 60 Gy in 25 fractions (Fig. 1A and B).

The median BT dose was 36 Gy in 6 fractions to the periphery of the HR-CTV, with a combined intracavitary/interstitial technique. The prescribed dose to the periphery of the HRCTV was 6 Gy. The radiation source (¹⁹²Ir) dwell time was adjusted using graphic optimization until the dose-volume constraints were optimally matched (Fig. 2). The planning aimed to deliver a minimum of 85 Gy to 90% of the HR-CTV in 2 Gy equivalent (EqD2), adding BT and external beam radiotherapy doses, and applying the linear quadratic model with an α/β ratio of 10 Gy.

It was planned that the patients would receive cisplatin (40 mg/m²) via intravenous infusion every week for 6 weeks during the course of external beam radiotherapy, and that patients with the following conditions would not receive concurrent chemotherapy: i) Elderly age (>70 years); ii) Performance Status score >2 (8); or iii) rejection of chemotherapy. Complete blood count tests were performed weekly and chemotherapy was withheld until resolution to at least grade 1 if patients presented with grade 3 or 4 hematological or gastrointestinal toxicity.

All patients were examined at 1 month post-radiotherapy, every 3 months during the first and second years, and every 6 months in the third year of follow-up. Follow-up investigations included clinical examination, Papanicolau smears, serum tumor marker (squamous cell carcinoma antigen) analysis and cross-sectional imaging (pelvic MRI and abdominal CT). Chest CT examination, supraclavicular lymph node ultrasound examination and bone scintigraphy were performed once a year to evaluate distant recurrence (lung, supraclavicular nodes and bone).

Follow-up abdominal CT and pelvic MRI were performed between 1 and 2 months after the completion of radiotherapy to evaluate the response to therapy. Complete response was defined as images and clinical examination resultsidentifying no evidence of local or regional nodal disease. Partial response was defined as any persistence of tumor at the site of local or regional nodes on the axial scan within 3 to 6 months after completion of radiotherapy. Local failure was defined as the recurrence or residual disease at the cervix, uterus or adjacent pelvic organs, e.g., parametria, bladder and vagina. Regional nodal relapse was defined as residual or recurrent, cancer in the pelvic or para-aortic lymph nodes (if the distal vagina was involved, inguinal lymph nodes were also considered regional relapse; otherwise, the nodes were considered distant metastases). Distant failure was defined as recurrence in non-regional lymph nodes (mediastinal and supraclavicular region) or hematogenous metastasis (including in the bones, liver and lungs). Failure was recorded on the basis of clinical examination and follow-up imaging (MRI/CT or PET/CT), and the majority of patients received biopsy confirmation.

Acute toxicity associated with radiotherapy was assessed in accordance with the RTOG acute radiation morbidity scoring criteria (9) and was defined as toxicity occurring between the initiation of treatment and 90 days after completion. Acute toxicity was assessed weekly during the course of radiotherapy, at the completion of RT and after 1 month; late effects were evaluated at each clinical visit. Adverse events for >90 days after the completion of treatment were graded in accordance with the RTOG late radiation morbidity scoring system (10).

Survival time and time to recurrence were measured from the date of initial radiation treatment. An unpaired t-test or χ² test was used to analyze the associations between patient characteristics, recurrence patterns and toxicities. The Kaplan-Meier estimator method was used to derive estimates of survival. Differences in OS and DFS were assessed using the log-rank test. OS time was calculated from the date of RT start to the date of mortality from any cause or last follow-up. The DFS time was calculated from the date of RT start to the date of disease progression, relapse or initiation of any new, unplanned, anticancer therapies associated with the disease. Disease-associated significant variables on univariate analysis were utilized for Cox's regression analysis to control the confounding factors for OS and DFS. P<0.05 was considered to indicate a statistically significant difference for all study outcomes. All statistical analyses were performed using SPSS (version 17.0; SPSS, Inc., Chicago, IL, USA). Results are presented as the mean ± standard deviation.

The total length of time for the two treatments ranged from 49 to 104 days (median, 61 days). The median duration of follow-up was 29.5 months (range, 7.4 to 50.6 months). A total of 19 out of the 107 patients included in the present study succumbed, including 5 of whom succumbed to concomitant disease (1 cerebral infarction, 1 heart failure, 1 myocardial infarction and 2 severe pulmonary infections). The mean survival time was 46.1 months, and the 2- and 3-year OS rates were 87.7 and 80.7%, respectively. A total of 29/107 patients (27.1%) exhibited failure at either local, regional node or distant sites. The mean DFS time was 41.2 months, and the 2- and 3-year DFS rates were 77.1 and 72.4%, respectively. The OS and DFS rates are presented (Fig. 3).

A total of 11 out of the 55 patients treated with EF-IMRT succumbed. The mean survival time was 35.0±1.40 months, and the 2- and 3-year OS rates were 81.5 and 79.4%, respectively. A total of 16 patients developed recurrence and the mean DFS was 31.2±1.93 months. The 2- and 3-year DFS rates were 73.7 and 61.0%, respectively.

A total of 8 patients treated with pelvic IMRT succumbed during the follow-up period. The mean survival time for pelvic irradiation was 45.4±1.67 months, and the 2- and 3-year OS rates were 90.2 and 82.3%, respectively. A total of 13 patients experienced failure and the mean DFS time was 40.7±2.42 months. The 2- and 3-year DFS rates for patients treated with pelvic IMRT were 78.3 and 73.7%, respectively. The differences in OS and DFS between EF-IMRT and pelvic IMRT patients were assessed using the log-rank test and no statistically significant differences were identified (Fig. 4A and B).

The univariate analysis revealed that patients with bulky tumors, a decreased nadir for hemoglobin concentration, increased treatment duration or increased level of LN metastasis were associated with diminished survival rates (Table II). The irradiation fields (EFor pelvic field) were entered and significant variables on univariate analysis were utilized for Cox's regression analysis to evaluate the effect of irradiation field on survival (Table III). It was revealed that patients treated with EF irradiation exhibited an improved prognosis compared with those treated with pelvic field when confounding factors, including the nadir-hemoglobin level, the most distant level of lymph nodes involved, and treatment duration, were controlled.

Of the 16 patients treated with EF-IMRT and who developed recurrence, 7 patients presented with more than one site of failure. A total of 7 of the 55 EF-IMRT patients (12.7%) developed local failure, 6 (10.9%) patients developed regional relapse (3 developed in para-aortic nodes) and 9 (16.4%) patients exhibited distant metastasis. Among the patients treated with pelvic IMRT, 13 patients relapsed and 4 patients presented more than one site of failure. A total of 6 of the 52 pelvic IMRT patients (11.5%) developed local failure, 3 (5.8%) developed regional failures (2 developed in para-aortic nodes) and 6 (11.5%) exhibited distant metastasis. No significant differences in the failure rate or proportion of recurrent sites between the two groups were identified in the patients (P=0.67 and P=0.88, respectively).

Acute toxicities are presented in Table IV. The two treatments were well-tolerated, with 19 (34.5%) and 10 (19.2%) patients experiencing grade 3 or greater acute toxicities for EF-IMRT and pelvic IMRT, respectively (P=0.048, Fisher's exact test). For EF-IMRT, 2 patients experienced severe nausea or vomiting, and 3 patients experienced severe diarrhea, which required pharmacological intervention. Of the 14 patients with grade 3 or greater hematological toxicities, 4 patients developed anemia and required a blood transfusion, and 10 patients with grade 3 or 4 leukopenia also presented with neutropenia. Of the patients treated with pelvic IMRT, 2 patients exhibited severely altered bowel habits, 2 possessed nadir-hemoglobin <70 g/l (normal range, 110–130 g/l) and 5 patients developed grade 3 leukopenia accompanied with neutropenia.

As for late toxicities, 5 patients treated with EF-IMRT and 4 treated with pelvic IMRT experienced grade 3 rectal bleeding requiring transfusion or surgery, and 1 patient treated with pelvic IMRT was diagnosed with grade 4 rectovaginal fistula as a result of local recurrence.