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.

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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. All 10 patients and 50 months for surviving patients. Of the metastatic lymph nodes administered >50.4 Gy remaining 14 patients, 12 died of tumor progression, one of (median=55.8 Gy) were controlled after treatment.

4850 Hata et al: RT for PALN Metastases from Cervical Cancer

Figure 2. Control of metastatic lymph nodes in 22 patients (dotted line) with para-aortic lymph node metastases from uterine cervical cancer, and in 80 metastatic lymph nodes (solid line).

leukopenia and thrombocytopenia were treated with radiation therapy plus chemotherapy. Regarding grade 3 or more therapy-related late toxicities, one patient developed grade 3 radiation proctitis at 6 months, and one developed grade 3 hemorrhagic cystitis and colitis at 7 and 26 months, respectively, after treatment. These damaged organs were included within the pelvic irradiation field for the primary tumors. These two patients received external irradiation plus intracavitary brachytherapy at total doses of 60 and 65.4 Gy at point A, respectively, along with Figure 1. Relationship between metastatic lymph node size and chemotherapy. radiation dose resulting in the control of para-aortic lymph node metastases from uterine cervical cancer following treatment with (a) Discussion radiation therapy plus chemotherapy and (b) radiation therapy alone. Four and three lymph nodes exhibited progression after radiation therapy plus chemotherapy and radiation therapy alone, respectively. Radiation therapy has been applied as curative treatment for uterine cervical cancer, comparable to surgery, and is available for patients considered to be medically inoperable because of old age or coexisting disease; however, it is usually limited to palliative use in patients with distant Additionally, none of the 35 lymph nodes ≤25 mm in metastases (5-7, 12, 13). Patients with para-aortic lymph diameter irradiated with 50 or 50.4 Gy exhibited progression. node metastases from uterine cervical cancer are considered Consequently, the 3-year metastatic lymph node progression- to be potentially curable, and aggressive treatment should be free rates were 78% for the cohort of 22 patients and 89% considered in these patients. Three-year overall survival rates considering the 80 metastatic lymph nodes (Figure 2). of 39-66% have been reported in these patients treated with external irradiation to metastatic para-aortic lymph nodes at Toxicity. There were no acute grade 3 or higher toxicities median total doses of 44.2-59.4 Gy in 1.5-2 Gy fractions, except for transient hematologic toxicities. Grade 3 with concurrent platinum-based chemotherapy (14-20). leukopenia developed in five patients and grade 4 leukopenia Some studies have also reported control of the metastatic in one. Grades 3 and 4 anemia were observed in one patient para-aortic lymph nodes themselves following radiation each, and grades 3 and 4 thrombocytopenia in two and one therapy. Kim et al. treated 29 patients with cervical cancer patient, respectively. All of the patients with grade 3 or more with para-aortic lymph node metastases with total doses of

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14.4-65 Gy (median=59.4 Gy) in 1.8 Gy fractions, along metastatic lymph nodes of 25 mm or less in diameter can be with platinum-based chemotherapy (15). Among these 29 controlled by a total radiation dose of 50.4 Gy, whereas the patients, 26, two, and one initially showed complete control of larger nodes may require higher doses of responses, partial responses, and stable disease, respectively, irradiation. A metastatic lymph node 28 mm diameter in one at 3 months after treatment, with an objective response rate patient progressed after chemotherapy plus radiation therapy of 97%. Wu et al. reported the control of para-aortic lymph at a dose of 50 Gy, indicating that a dose of 50 Gy may be node metastases in 21 patients treated with irradiation at total insufficient to control metastatic lymph nodes of this size, doses of 27-57.6 Gy (median=45 Gy) in 1.8-2 Gy fractions, even with additional chemotherapy. Our previous study along with concurrent cisplatin-based chemotherapy in most investigated the relationship between metastatic lymph node patients (20). The 3-year progression-free rates considering size and the radiation dose needed to control pelvic lymph the metastatic para-aortic lymph nodes were 58% and 100% node metastases from uterine cervical cancer (33). The results in patients treated with ≤45 Gy and ≥50.4 Gy, respectively. demonstrated that a total dose of 50.4 Gy was sufficient to On the basis of this result, the authors recommended the control metastatic pelvic lymph nodes less than 24 mm in delivery of at least 50.4 Gy to control metastatic para-aortic diameter, whereas higher doses (55.8 Gy as an optimal dose) lymph nodes. In the present study, the initial objective were acceptable for larger nodes. These previous results are response rate of the metastatic para-aortic lymph nodes was compatible with those of the present study, suggesting that 100%, and all lymph nodes administered >50.4 Gy were the optimal radiation doses for controlling para-aortic and controlled. Our results are therefore compatible with those pelvic lymph node metastases may be similar. of previous reports. However, high-dose irradiation to the abdomen in patients However, the optimal radiation regimens for para-aortic with para-aortic lymph node metastases from uterine cervical lymph node metastases remain unclear. To the best of our cancer can cause severe complications, such as ulcers, knowledge, no studies have assessed the relationship stenosis and perforation of the intestine and ileus (34, 35). It between metastatic lymph node size and the radiation dose has been reported that 10% of patients who received required to control para-aortic lymph node metastases from irradiation at the maximum dose of 55 Gy to the small uterine cervical cancer. We defined para-aortic lymph nodes intestine developed grade 3 or more late small intestinal >10 mm in short-axis diameter on CT as metastatic, a toxicities within 5 years after irradiation (36). There is a criterion which has been most widely used for lymph node close relationship between radiation dose and volume metastasis from cervical cancer (7, 21, 22). The reported administered to the small intestine and the incidence of accuracy, sensitivity, specificity, and positive and negative radiation-induced complications. The 5-year incidences of predictive values associated with this cut-off are 67-94%, 50- obstruction and perforation of the small intestine after 80%, 79-97%, 64-80% and 69-97%, respectively, as irradiation with 50 Gy and 60 Gy in conventional fractions confirmed by histological findings (23-27). Generally, raising through a radiation field of 10 cm2 have been estimated to the threshold of lymph-node size increases the specificity be 5% and 50%, respectively (37). In addition, a larger and positive predictive value and reduces the sensitivity and volume of the duodenum receiving ≥55 Gy led to higher negative predictive value. A threshold of 15 mm has been rates of duodenal toxicity. Doses of ≥55 Gy given to less associated with positive predictive values on CT of 75-100% than 15 cm3 of the duodenum and more than this were (28-30). In the present study, 71 out of the 80 lymph nodes associated with 3-year rates of grade 2 or more late duodenal defined as metastatic were 15 mm or more in diameter, toxicities of 7% and 49%, respectively (38). Furthermore, providing further evidence that many of the enlarged lymph chemotherapy potentially increases radiation toxicity to nodes reviewed in the present study were true positives. normal tissues because of an enhanced cytotoxic effect (39, Furthermore, PET has been reported to allow more accurate 40). Radiation doses to the abdomen should therefore be detection of lymph node metastasis, but was not regarded as minimized. indispensable in our study (31, 32). All patients in the study were treated with conventional Radiation therapy controlled 73 out of 80 metastatic para- radiation therapy. However, intensity-modulated radiation aortic lymph nodes in 18 out of our 22 patients. The four therapy (IMRT) using an advanced technique has recently patients with lymph node progression had a total of seven been tried in patients with para-aortic lymph node enlarged para-aortic lymph nodes measuring 20-50 mm in metastases from uterine cervical cancer. IMRT produces diameter before treatment, all of which progressed after better dose localization compared with conventional radiation therapy with total doses of ≤50.4 Gy. In contrast, radiation therapy, making it possible to reduce the lymph nodes administered more than 50.4 Gy (median= irradiation dose and volume for critical organs, including the 55.8 Gy) were controlled after treatment. Additionally, no intestine, while increasing the dose delivered to the target lymph nodes 25 mm or less in diameter irradiated with 50 or (38, 41). IMRT has been reported to reduce intestinal 50.4 Gy exhibited progression. These results suggest that toxicities significantly when used to treat uterine cervical

4852 Hata et al: RT for PALN Metastases from Cervical Cancer cancer with para-aortic lymph node metastases (38, 42). 3 Benedetti-Panici P, Maneschi F, Scambia G, Greggi S, Cutillo Jensen et al. treated 21 patients with para-aortic lymph node G, D'Andrea G, Rabitti C, Coronetta F, Capelli A and Mancuso metastases from cervical cancer with radiation therapy with S: Lymphatic spread of cervical cancer: an anatomical and pathological study based on 225 radical hysterectomies with a median total dose of 55.4 Gy in 1.8-2.2 Gy fractions and systematic pelvic and aortic lymphadenectomy. Gynecol Oncol concurrent weekly chemotherapy with cisplatin (42). They 62: 19-24, 1996. were treated with IMRT, which caused no grade 3 or more 4 FIGO Committee on Gynecologic Oncology: FIGO staging for late intestinal toxicities at a median follow-up period of 22 carcinoma of the vulva, cervix, and corpus uteri. Int J Gynaecol months after treatment. Advanced radiation therapy such as Obstet 125: 97-98, 2014. 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