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Radiation Therapy for Para-Aortic Lymph Node Metastasis from Uterine Cervical Cancer

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Radiation Therapy for Para-Aortic Lymph Node Metastasis from Uterine Cervical Cancer ANTICANCER RESEARCH 35: 4849-4854 (2015) Radiation Therapy for Para-Aortic Lymph Node Metastasis from Uterine Cervical Cancer MASAHARU HATA1,3, ETSUKO MIYAGI2,4, IZUMI KOIKE3, REIKO NUMAZAKI4, MIKIKO ASAI-SATO4, TAKEO KASUYA3, HISASHI KAIZU3, YUKI MUKAI3, FUMIKI HIRAHARA4 and TOMIO INOUE3 Divisions of 1Radiation Oncology and 2Gynecologic Oncology, Department of Oncology, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan; Departments of 3Radiology and 4Obstetrics and Gynecology, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan Abstract. Aim: To evaluate the efficacy of radiation therapy Uterine cervical cancer is the fourth most common malignancy for para-aortic lymph node metastases from uterine cervical in women worldwide, with an estimated 528,000 new cases and cancer and to identify an optimal radiation regimen. Patients 266,000 deaths per year (1). The majority (approximately 85%) and Methods: A total of 80 metastatic para-aortic lymph of cases occur in developing countries, where it is the most nodes, ranging from 11-50 mm (median=20 mm) on computed common malignancy in women, accounting for almost 12% of tomography, in 22 patients with squamous cell carcinoma of all female malignancies. Uterine cervical cancer is often the uterine cervix were initially treated with radiation therapy. accompanied by metastasis to the para-aortic lymph nodes, Total radiation doses for para-aortic lymph node metastases which occurs in about 5% of patients diagnosed with stage I, were 40-61.2 Gy (median=50.4 Gy) in 1.8-2 Gy fractions. 16% with stage II, and 25% with stage III disease, based on the Results: Eight out of the 22 patients remained alive at a International Federation of Gynecology and Obstetrics staging median follow-up of 32 months. Seven irradiated lymph nodes, system (2-4). Although para-aortic lymph node metastasis is 20-50 mm in diameter, in four patients progressed after defined as distant metastasis, these patients are frequently irradiation at total doses of 44-50.4 Gy. No metastatic lymph treated with radiation therapy, which can lead to cure (5-7). nodes administered >50.4 Gy (median=55.8 Gy) exhibited However, few studies to date have included detailed evaluations progression after irradiation. All metastatic lymph nodes ≤25 of radiation therapy regimens for controlling para-aortic lymph mm in diameter irradiated with 50 or 50.4 Gy were controlled. node metastases from uterine cervical cancer, particularly the The 3-year lymph node progression-free rates were 78% in the relationship between metastatic lymph node size and the cohort of 22 patients and 89% considering all 80 metastatic required radiation dose. We, therefore, retrospectively reviewed lymph nodes. Apart from transient hematological reactions, outcomes in patients with uterine cervical cancer and para-aortic two patients developed grade 3 or more therapy-related lymph node metastases treated with radiation therapy, and toxicities, including radiation proctitis in one and hemorrhagic discuss the optimal radiation regimen. cystitis and colitis in another. Conclusion: Radiation therapy can effectively control para-aortic lymph node metastases in Patients and Methods patients with uterine cervical cancer. A total dose of 50.4 Gy in 1.8 Gy fractions is sufficient to control metastatic lymph Patients. Between September 1996 and December 2012, 22 patients nodes ≤25 mm in diameter, whereas a higher dose with uterine cervical cancer and para-aortic lymph node metastases received radiation therapy as initial treatment at our institution. (approximately 55.8 Gy) may be required for larger nodes. Eligibility criteria were histopathologically confirmed squamous cell carcinoma and no distant metastasis in other visceral organs. Clinical stage was assessed by chest X-ray and computed tomography (CT), abdominal CT, and pelvic CT and/or magnetic resonance imaging. All Correspondence to: Masaharu Hata, MD, Division of Radiation patients had para-aortic lymph node metastases, and were clinically Oncology, Department of Oncology, Yokohama City University diagnosed with stage IVB disease, based on the TNM classification Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, defined by the Union for International Cancer Control (8). Para-aortic Yokohama, Kanagawa 236-0004, Japan. Tel: +81 457872696, Fax: lymph nodes >10 mm in short-axis diameter on CT were defined as +81 457860369, e-mail: [email protected] metastatic. The 22 patients had a total of 80 metastatic lymph nodes (1-10 per patient), with a maximum diameter 11-50 mm (median=20 Key Words: Cervical cancer, para-aortic lymph node metastasis, mm). 18F-Fluorodeoxyglucose positron-emission tomography (PET) radiation therapy, squamous cell carcinoma, uterine cervix. was also used to evaluate lymph node metastasis in 7 patients. 0250-7005/2015 $2.00+.40 4849 ANTICANCER RESEARCH 35: 4849-4854 (2015) Patient characteristics are shown in Table I. Informed consent Table I. Patient characteristics. was obtained from all patients before treatment. Characteristic Value Radiation therapy. All 22 patients initially received external irradiation to the whole pelvis in antero-posterior opposed fields or Number of patients 22 antero-posterior and bilateral fields (box fields) with 6-15 MV X-rays. Median age (range), years 65 (32-83) Patients received 1.8-2 Gy per day, five times per week, to a total dose Performance status (ECOG) of 45-50.4 Gy (median=50.4 Gy) in 25-28 fractions (median=28 09 fractions). All but three out of the 22 patients also received high-dose- 19 24 rate (HDR) intracavitary brachytherapy along with external irradiation Median max. primary tumor diameter (range), mm 57 (38-95) to treat the primary cervical tumors. Total doses of 15-30 Gy T Category (median=20 Gy) in 3-6 once-weekly fractions (median=4 fractions) T1b 1 of 3.5-6 Gy were delivered to point A using an HDR Ir-192 source T2b 1 (9). Although intracavitary brachytherapy was considered for the T3b 17 control of primary tumors with higher doses in all patients, it was T4 3 abandoned in the remaining three patients because of dementia or N Category technical difficulties. The primary tumors in these three patients were N0 1 treated with external irradiation alone at total doses of 50.4-54 Gy in N1 21 28-30 fractions. The total doses administered to all 22 patients were Para-aortic lymph node metastasis therefore 50.4-80.4 Gy (median=68.7 Gy) at point A. Total number per patient Para-aortic lymph node irradiation was started either after or 14 during pelvic irradiation. Doses of 40-50.4 Gy in 20-28 fractions were 26 delivered to the para-aortic lymph node area in all patients. The ≥3 12 superior and inferior borders of the radiation field were mostly set at Median max. diameter (range), mm 20 (11-50) the level of the top of the Th12 vertebra and the L4/5 interspace, Chemotherapy which almost corresponded to the superior border of the pelvic Yes 13 radiation field, respectively. This treatment was followed by a local No 9 radiation boost to the metastatic lymph nodes at doses of 3.6-10.8 Gy in eight patients. Total doses of 40-61.2 Gy (median=50.4 Gy) in ECOG, Eastern Cooperative Oncology Group. 20-34 fractions (median=28 fractions) were thus delivered to the metastatic lymph nodes. The overall treatment time from the beginning of pelvic irradiation to the completion of para-aortic lymph node irradiation was 45-130 days (median=85 days). intracranial hemorrhage, and one of suffocation as a result of Thirteen out of the 22 patients also received chemotherapy, with mis-swallowing. There were no therapy-related mortalities. 2 most receiving concurrent intravenous cisplatin (40 mg/m ) once per Although the study was designed to follow-up all patients week during pelvic irradiation. until study end or death, contact with three patients was lost Follow-up and evaluation criteria. Patients were examined by pelvic 3, 8 and 110 months after radiation therapy. CT within 1 month after completion of irradiation, and had subsequent follow-up CT scans at 3- to 12-month intervals. Irradiated metastatic Control of para-aortic lymph node metastasis. Following lymph nodes that did not progress were considered controlled. irradiation, all 80 metastatic lymph nodes in the 22 patients Acute and late toxicities associated with radiation therapy were macroscopically disappeared or were markedly reduced in evaluated using the Radiation Therapy Oncology Group (RTOG) size on CT, making the initial objective response rate 100%. acute radiation morbidity scoring criteria and the RTOG/European However, seven metastatic lymph nodes of 20-50 mm in Organization for Research and Treatment of Cancer late radiation morbidity scoring scheme, respectively (10). Acute toxicities were diameter in four patients progressed at 7-20 months after defined as radiation-induced toxicities occurring within 3 months irradiation with total doses of 44-50.4 Gy, including one (20 after the beginning of radiation therapy, and late toxicities were mm) with 44 Gy, four (22, 26, 29 and 50 mm) with 45 Gy, those occurring after 3 months. one (28 mm) with 50 Gy, and one (30 mm) with 50.4 Gy Actuarial disease-control rates were calculated from the beginning (Figure 1). Of these four patients with progression, three had of radiation therapy according to the Kaplan–Meier method (11). All four metastatic lymph nodes (20, 26, 28 and 30 mm) and statistical analyses were performed using the statistical software IBM received radiation therapy plus chemotherapy. Another SPSS version 22 (IBM, Armonk, NY, USA). patient had three metastatic lymph nodes (22, 29 and 50 mm) Results and was treated with radiation therapy alone. Of the 52 metastatic lymph nodes administered doses of ≥50 Gy, only Survival. Eight out of the 22 patients remained alive at a two, 28 and 30 mm in diameter, exhibited progression after median follow-up of 32 months (range=3-131 months) for all irradiation with 50 and 50.4 Gy, respectively.
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