Treatment outcomes of extended-field radiation therapy and the effect of concurrent chemotherapy on uterine cervical cancer with para-aortic lymph node metastasis

This retrospective study received approval from the internal review boards of the participating institution (IRB No. 4-2014-0162). Between April 1987 and December 2012, 123 patients with cervical cancer and PAN metastasis were treated with EFRT at our institution. Among them, 33 patients were excluded if any of the following conditions were met: (1) stage IVB, (2) distant nodal metastasis in inguinal, mediastinal or supraclavicular lymphatics, (3) salvage, palliative, or postoperative RT, (4) induction or post-RT chemotherapy, (5) incomplete RT due to patient refusal. Consequently, 90 patients were included in this retrospective study. Clinical staging was based on the FIGO stage classifications updated in 2009 [11]. The procedure for staging included a detailed history and a physical examination, common laboratory tests, standard chest radiographs, intravenous pyelograms, barium enemas, X-ray examination of the lungs and skeleton, cystoscopies, and sigmoidoscopies. All patients underwent computed tomography (CT) (57.8%) or magnetic resonance imaging (MRI) (63.3%) scans to evaluate pelvic or para-aortic lymph node involvement. Positron emission tomography (PET) or PET-CT scans were performed in 21 patients (23.3%). In the image interpretation of CT or MRI, the principal criterion for metastatic node involvement was the axial diameter of the lymph node. The presence of lymph nodes larger than 1 cm in the short-axis dimension was considered to indicate metastatic node involvement. Additionally, we regarded central necrosis as a significant criterion for metastatic disease within the lymph node [12]. In the image interpretation of PET or PET-CT, a malignant lymphadenopathy was defined as follows: 1) fluorodeoxyglucose (FDG) accumulation greater than liver accumulation or similar to brain cortex accumulation, or 2) standardized uptake value of a lesion that corresponded to CT and did not decrease on the delayed PET image compared with the initial PET image [13]. Para-aortic lymph nodes were surgically assessed in 7 patients (7.8%). Histologic classification was based on the World Health Organization classifications (Geneva, Switzerland).

All patients received a combination of external EFRT and high-dose-rate intracavitary brachytherapy (HDR-ICR). We used the box technique with parallel opposing fields for 87 patients or the two-field technique with antero-posterior fields for 3 patients. For para-aortic irradiation, we defined the T11-T12 or T12-L1 interspace covering the entire PAN as the superior border, 2 cm from the front of the vertebral body or enlarged lymph nodes as the anterior border, and the midline of the vertebral body as the posterior border, respectively. For whole pelvic irradiation, we defined the inferior border of the obturator foramen (if distal vaginal was not involved) or 2 cm below the lowest extent of the primary tumor (if there was distal vaginal invasion) as the inferior border, and 1.5 cm to 2 cm from the true bony pelvis as the lateral border in AP-PA fields. External EFRT was delivered using a 10-MV linear accelerator with a dose of 1.8-2 Gy per fraction, 5 times per week. Midline shielding with a 4 cm-width was performed after the delivery of 26.0 to 45 Gy based on treatment response. This was followed by HDR-ICR using a remote afterloading system with a Ralstron 303 Co-60 source (Shimadzu, Kyoto, Japan) from 1979 to 1997, or a Gamma-Med II Ir-192 source (Sauerwein, Haan, Germany) from 1989 to 2006, or Multisource® Ir-192 source (Eckert & Ziegler BEBIG, Berlin, Germany) from 2007 onward. The total dose of HDR-ICR was 20–48 Gy, with 3 or 5 Gy per fraction, which was prescribed to point A. Overall, a 3 Gy per fraction with a median fraction number of 10 (range, 8–16) was prescribed for 43 patients and a 5 Gy per fraction with a median fraction number of 6 (range, 4–8) was administered to the others. After the completion of HDR-ICR, patients were administered a second course of external EFRT with midline shielding to a total external beam dose of 45 to 54 Gy. For patients with persistent residual disease, which was identified on pelvic examination and imaging studies performed at 1 month after planned EFRT and HDR-ICR, boost irradiation to the parametrium, pelvic wall, and involved node was performed. The median dose of boost irradiation was 9 Gy (range, 5.4-16 Gy).

Platinum single-agent or platinum-based doublet regimens were used. For concurrent chemoradiation (CCRT), protocols included two treatment schemes. One scheme was composed of three chemotherapy cycles administered at the beginning of the first, fourth, and seventh weeks of RT [14], and the regimen consisted of cisplatin (70 mg/m²) or carboplatin (area under the curve (AUC), 4) followed by five consecutive daily infusions of 5-FU (1000 mg/m²/day). Weekly administration of cisplatin (40 mg/m²) or carboplatin (AUC, 2) during RT has been performed since the publication of randomized trials [15].

During treatment, adverse effects and performance levels were monitored weekly. After completion of treatment, all patients were evaluated at 1 month and every 3 months for the first 2 years, and every 6 months thereafter. Acute treatment-related hematologic toxicities were defined according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. Acute toxicities were evaluated from the start of treatment to 3 months following the completion of treatment. Depending on the severity and duration of toxicity, treatment was interrupted until the patient recovered. Late treatment-related toxicities were assessed using the Late Radiation Morbidity Scoring Scheme of the Radiation Therapy Oncology Group and the European Organization for Research and Treatment of Cancer. Late radiation toxicities developing later than 6 months after the completion of treatment were grouped into rectal, bladder, small bowel, and other complications.

We defined a complete remission (CR) as 100% decrease of gross tumor on clinical evaluation or radiologic images. Partial response (PR) and progressive disease (PD) were defined as ≥ 50% decrease and > 25% increase of primary gross tumor, respectively. Anything else was categorized as stable disease. We evaluated treatment responses by performing history taking, physical and pelvic examinations, and imaging studies, such as MRI or CT scan, at 3 months after completion of all treatments. The follow-up imaging studies were performed routinely at 1, 3, 6, 12, 18, and 24 months after treatment completion, and once a year thereafter. We defined local recurrence as any relapse or persistent disease at the cervix, vagina, parametrium, or pelvic wall. Regional recurrence was defined as node relapse within the RT field. Although PAN relapse is considered as a distant metastasis in the TNM staging system, PAN relapse was classified as a regional recurrence in this study. We defined distant metastasis as relapse outside the RT field.

Total dose to point A (Gy) was calculated by combining the dose of external beam irradiation before midline shielding and the total dose to point A in HDR-ICR. Overall actuarial survival (OS) and progression-free survival (PFS) were calculated using the Kaplan–Meier method and differences in survival rates were compared by the log-rank test. The OS time was calculated from the date of RT start to the date of death or last follow-up. The PFS time was calculated from the date of RT start to the date of disease progression, relapse, initiation of new unplanned anticancer therapy, disease-related death, or last follow-up. We analyzed prognostic factors for OS and PFS using a Cox regression method. Significant variables on univariate analysis were utilized for multivariate analysis to establish independent prognostic factors for OS and PFS. Differences in nominal variables were compared using Pearson’s χ² test or Fisher's exact test. We analyzed difference in continuous variables using the Mann–Whitney U test. We considered statistical significance as p value ≤ 0.05.