Outcome of Radiation Therapy for Stage IVB Uterine Cervical Cancer With Distant Lymph Nodes Metastases; Sequential Irradiation for Distant Lymph Nodes Metastases

Patients and Methods

We retrospectively reviewed the medical records of 26 patients who underwent external beam RT, with or without concurrent chemotherapy, for UCC with distant LN metastases without organ metastases at our Institution between July 2004 and December 2018. All patients were eligible for this study. Patients who were considered to have stage IIIC2 UCC with only PALN metastases and patients with recurrent cervical cancer were excluded. The clinical stage was based on physical examination, basic laboratory studies, chest X-ray, contrast-enhanced computed tomography (CT) of the neck to the pelvis, and magnetic resonance imaging of the pelvis. One patient was unable to undergo magnetic resonance imaging because of a tattoo. If necessary, bladder and rectum status were determined by cystoscopy and colonoscopy, respectively. All patients were examined before treatment by gynecologists and radiation oncologists, and their disease was classified according to the Union for International Cancer Control staging system (11). Their disease characteristics are summarized in Table I. All patients had both pelvic LN metastases and another site of distant LN metastases: 19 had SCLN metastases, nine had inguinal LN metastases, four had axillary LN metastases, and three had metastases at other sites including the mesentery and mediastinum. Eleven patients had only SCLN metastases. Patients who were considered to have stage IIIC2 UCC with only PALN metastases and patients with recurrent cervical cancer were excluded. This study was approved by our Institutional Review Board (IRB number, B200600006) and informed consent was obtained from all patients before treatment.

Treatment. All 26 patients received three-dimensional RT of the whole pelvic radiation field using 2-4 beams with 15-MV X-rays. Eight patients received whole pelvic RT (WPRT), including bilateral inguinal LN regions, using two beams. The gross tumor volume was defined as the volume of the primary tumor and involved LNs. The clinical target volume (CTV) was defined as the volume of the primary tumor plus a 5 mm margin that included the pelvic LNs and the parametrium. The CTV for LNs included the common, external, and internal iliac, and obturator LN regions and extended to the level of the L4-5 interspace. The CTV for LNs in these eight patients additionally included bilateral inguinal LN regions. The caudal edge of the radiation field was defined according to the extent of primary disease invasion. The planning target volume was delineated with a 10-15-mm margin around the CTV. Normal structures, including the bladder, rectum, small bowel, and femoral heads, were contoured as organs at risk in the radiation field.

The median prescribed total radiation dose to the pelvis was 50 (range=50-56) Gy, the fraction size was 1.8-2 Gy, and fractions were delivered on 5 consecutive days per week. Fifteen patients (57.7%) received high-dose-rate intracavitary brachytherapy (HDR-ICBT). The remaining patients did not receive HDR-ICBT because their cervical tumors did not shrink sufficiently to warrant intracavitary application or they had comorbidity (dementia, depression), or poor performance status (PS). HDR-ICBT was performed using Ir-192 with microSelectron-HDR (Nucletron, Veenendaal, the Netherlands). The standard regimen of HDR-ICBT in our Institution is 5 Gy per fraction for point A (12).

The median dose of HDR-ICBT was 15 Gy in three fractions (range, 10-25 Gy, in 2-5 fractions). Five patients with pelvic or inguinal LN involvement, or both, received an additional boost of up to 54-59.4 Gy to those lesions following WPRT. Two patients had an additional boost of up to 56 and 56.4 Gy for their primary tumor. The median duration of all treatments, including external beam radiation therapy and HDR-ICBT, was 46 (range=32-70) days. All patients completed the planned RT for their primary tumors. The total equivalent dose in 2 Gy fractions (EQD2) to the primary tumor (α/β=10) was calculated from a linear-quadratic model. The median EQD2 to the primary tumor was 63 (range=48.4-72.4) Gy.

Sixteen out of the 26 patients had chemotherapy concomitant with RT, consisting of weekly cisplatin (n=15; 40 mg/m² body surface area) or paclitaxel (135 mg/m²) and carboplatin (area under the curve 5, Calvert’s formula) in 1. The reasons for the remaining 10 patients not receiving chemotherapy were as follows: Renal dysfunction in four; poor general condition (poor PS), old age, or comorbidity in 5; and patient refusal in one.

At initial diagnosis of UCC, 21 patients had PALN metastases, and 15 of them received RT to the PALN region immediately after initial WPRT within 2 months. The median RT dose was 52.2 (range=40-60) Gy, delivered using two or four 15-MV beams. In the remaining six patients, the involved PALNs had become unclear after concurrent chemoradiation therapy in five, and induction chemotherapy in one for the primary tumor, and they did not receive PALN RT. One patient developed PALN metastases 6 months after the initial treatment, and she received RT of 54 Gy in 27 fractions.

At initial diagnosis, 19 patients had left SCLN metastases (Table I), and 14 of them received RT for the metastases at a median dose of 50 (range=40-60) Gy. RT was delivered using the parallel-opposed (antero-posterior) field at 6 MV. Thirteen patients received RT within 2 months after initial WPRT, and only one patient received RT at the same time as initial WPRT. The remaining five patients did not receive RT for SCLN metastases. In three who received initial concurrent chemoradiotherapy for the primary tumor and one who received induction chemotherapy, their SCLNs became undetectable after initial treatment; therefore, they did not undergo RT of the SCLN region. The other patient developed disseminated intravascular coagulation soon after initial treatment and missed the chance of RT for SCLN metastases. Nine patients had inguinal LN metastases, and eight received RT for the metastases at a median dose of 54.9 (range=50.4-59.4) Gy, at the same time as initial WPRT. The inguinal LNs were usually irradiated by enlarging the field of pelvic RT. One patient did not receive RT for inguinal LNs because she had SCLN metastasis and curative treatment was considered difficult. One out of four patients who had axillary LN metastases received RT by enlarging the field of SCLN, and in the remaining three patients, axillary LN metastases became undetectable after initial treatment.

Evaluation criteria and statistical analysis. Responses were evaluated by clinical examination and CT from the neck to the pelvis within 4-6 weeks following the completion of treatment. Tumor responses were assessed using the Response Evaluation Criteria in Solid Tumors (RECIST ver. 1.1) (13). Treatment-associated toxicity was evaluated using the Common Terminology Criteria for Adverse Events v4.0 (14). Acute toxicity was defined as treatment-related adverse events that occurred within 3 months after initiation of treatment, and late toxicity as adverse events occurring after 3 months. OS, cause-specific survival (CSS), local control for primary tumor (LC), and PFS rates from initiation of treatment were calculated with Kaplan-Meier curves. Differences between curves were tested by the log-rank test. Analyses of prognostic factors used univariate and multivariate Cox proportional-hazards regression models, with SPSS for Windows version 23.0 (IBM, Armonk, NY, USA). A value of p<0.05 was considered significant.