Phase II study of radiation therapy combined with weekly nedaplatin in locally advanced uterine cervical carcinoma (LAUCC): Kitasato Gynecologic Radiation Oncology Group (KGROG 0501) - initial analysis

Objective: Locally advanced uterine cervical carcinoma (LAUCC) treated with chemoradiotherapy is considered to be the standard treatment regimen. However, no evidence of its efficacy and safety has been obtained from the Japanese population. Furthermore. the total dose of Japanese radiation therapy protocol is less than that of the USA which indicated that chemoradiotherapy for LAUCC is better than radiation therapy alone by phase III clinical trials. Thus, the current phase II study was designed to evaluate chemoradiotherapy with a lower radiation dose for LAUCC using weekly nedaplatin effectively and safely in the Japanese population. Nedaplatin is a platinum drug and no hydration is required to infuse patients because it is less toxic on renal function. If this phase II trial is successful, chemoradiotherapy for LAUCC in out-patient clinics could be possible. Patients and Methods: Patients registered in the current study were found to have LAUCC based on the following criteria i) pathologically proven squamous cell carcinoma or adenocarcinoma, ii) FIGO clinical Stage Ib, IIa, IIb with bulky tumor (diameter > 40 mm assessed by pelvic magnetic resonance imaging) or pelvic lymph node swelling (diameter > 10 mm assessed by pelvic computed tomography); iii) FIGO clinical Stage IIIa, IIIb and IVa with no paraaortic lymph node swelling (diameter > 10 mm) observed by abdominal computed tomography; iv) age: 20-75 years; v) performance status: 0-2. The treatment protocol was as follows: Radiation therapy in a combination of external beam radiation therapy (total dose: 50 Gy-52 Gy/25-27 fractions with central shielding after 30-32 Gy) with high-dose rate intracavitary irradiation (24-30 Gy/4-6 fractions to point A). Chemotherapy applied in the current study was weekly nedaplatin infused intravenously (30 mg/mm(2)/time, once a week, total 150 mg/mm(2)/5 weeks). Sample size in the current study was 45 LAUCC patients recruited for three years at a single institution. This protocol was permitted by the ethics committee of Kitasato University Hospital. Results: Ten patients were registered in this study between June 2005 and March 2006. The median age was 57.5 years (range 36-73). PS0 was five and PS1 was five. As for clinical stage, nine were IIIb and only one was IIb. Nine patients were proven to have squamous cell carcinoma and one adenocarcinoma. The median maximum tumor diameter was 62.5 mm (range 30-100 mm). As for initial response, eight had CR and two had PR (100% response rate). As for hematological acute morbidity, three were grade 2, six were grade 3, and one was grade 4. Conclusions: This initial analysis of the phase II study confirmed that concurrent chemoradiotherapy using nedaplatin is safe and efficacious, thus we decided to undergo further studies.

Concurrent chemoradiotherapy; High-dose rate intracavitary brachytherapy (HDR-ICBT); Nedaplatin; Locally advanced uterine cervical carcinoma

[1]Whitney C.W., Sause W., Bundy B.N., Malfetano J.H., Hannigan E.V., Fowler W.C Jr. et al.: “Randomized comparison of fluorouracil plus cisplatin versus hydroxyurea as an adjunct to radiation therapy in Stage IIB-IVA carcinoma of the uterine cervix with negative paraaortic lymph nodes a Gynecologic Oncology Group and Southwest Oncology Group study”. J. Clin. Oncol., 1999, 17, 1339.

[2] Morris M., Eifel P.J., Lu J., Grigsby P.W., Levenback C., Stevens R.E. et al.: “Pelvic radiation with concurrent chemotherapy compared with pelvic and para-aortic radiation for high-risk cervical cancer”. N. Eng. J. Med., 1999, 340, 1137.

[3] Rose P.G., Bundy B.N., Watkins E.B., Thigpen J.T., Deppe G., Maiman M.A. et al.: “Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer”. N. Eng. J. Med., 1999, 340, 1144.

[4] Nakano T., Kato S., Ohno T., Tsujii H., Sato S., Fukuhisa K. et al.: “Long-term results of high-dose rate intracavitary brachytherapy for squamous cell carcinoma of the uterine cervix”. Cancer, 2005, 103, 92.

[5] Nag S., Erickson B., Thomadsen B., Orton C., Demanes J.D., Petereit D.: “The American Brachytherpay Society recommendations for high-dose-rate brachytherapy for carcinoma of the cervix”. Int. J. Radiat. Oncol. Biol. Phys., 2000, 48, 201.

[6] Toita T., Kakinohana Y., Ogawa K., Adachi G., Moromizato H., Nagai Y. et al.: “Combination external beam radiotherapy and high-dose-rate intracavitary brachytherapy for uterine cervical cancer: analysis of dose and fractionation schedule”. Int. J. Radiat. Oncol. Biol. Phys., 2003, 56, 1344.

[7] Green J.A., Kirwan J.M., Tierney J.F., Symonds P., Fresco L., Collingwood M. et al.: “Survival and recurrent after concomitant chemotherapy and radiotherapy and radiotherapy for cancer of the uterine cervix: a systemic review and meta-analysis”. Lancet, 2001, 358, 781.

[8] Komaki R., Seiferheld W., Ettinger D., Lee J.S., Movsas B., Sause W.: “Randomized phase II chemotherapy and radiotherapy trial for patients with locally advanced inoperable non-small-cell lung cancer: long-term follow-up of RTOG 92-04”. Int. J. Radiat. Oncol. Biol. Phys., 2002, 53, 548.

[9] Ohtsu A., Boku N., Muro K., Chin K., Muto M., Yoshida S. et al.: “Definitive chemoradiotherpay for T4 and/or M1 lymph node squamous cell carcinoma of the esophagus”. J. Clin. Oncol., 1999, 17, 2915.

[10] Worden F.P., Moon J., Samlowski W., Clark J.I., Dakhil S.R., Williamson S. et al.: “A phase II evaluation of a 3-hour infusion of paclitaxel, cisplatin, and 5-fluorouracil in patients with advanced or recurrent squamous cell carcinoma o the head and neck: Southwest Oncology Group study 0007”. Cancer, 2006, 107, 319.

[11] Kodaira T., Fuwa N., Kamata M., Frurtani K., Tachibana H., Yamazaki T.: “Single-institute phaseI/II trial of alternating chemotherapy with 5-FU and nedaplatin for esophageal carcinoma”. Anticancer Res., 2006, 26, 471.

[12] Nemoto K., Matsushita H., Ogawa Y., Takeda K., Takahashi C., Britton K.R. et al.: “Radiation therapy combined with cisdiammine-glycolatoplatinum (nedaplatin) and 5-fluorouracil for untreated and recurrent esophageal cancer”. Am. J. Clin. Oncol., 2003, 26, 46.

[13] Idei T., Sakamoto H., Nakajima Y., Hiraiwa Y., Takami N., Chishima F. et al.: “Concurrent weekly nedaplatin-based radiotherapy fo high risk, recurrent and advanced cervical cancer”. Gan To Kagaku Ryoho, 2003, 30, 505.

[14] Niibe Y., Hayakawa K., Tsunoda S., Kanai T., Imai M., Arai M. et al.: “Phase II study of radiation therapy combined with weekly nedaplatin in locally advanced uterine cervical carcinoma: Kitasato Gynecologic Radiatin Oncology Group (KGROG0501)”. Jpn. J. Clin. Oncol., 2007, 37, 70.

[15] Ohno T., Kato S., Wakatsuki M., Noda S.E., Murakami C., Nakamura M. et al.: “Incidence and temporal pattern of anorexia, diarrhea, weight loss, and leukopenia in patients with cervical cancer treated with concurrent radiation therapy and weekly cisplatin: comparison with radiation therapy alone”. Gynecol. Oncol., 2006, 103, 94.

[16] Toita T., Moromizato H., Ogawa K., Kakinohana Y., Mehama T., Kanazawa K. et al.: “Concurrent chemoradiotherapy using highdose- rate intracavitary brachytherapy for uterine cervical cancer”. Gynecol. Oncol., 2005, 96, 665.