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Cisplatin, Tegafur‑Uracil and Leucovorin Plus Mitomycin C

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Cisplatin, Tegafur‑Uracil and Leucovorin Plus Mitomycin C Original Article 229 Cisplatin, Tegafur‑Uracil and Leucovorin plus Mitomycin C: An Acceptably Effective and Toxic Regimen for Patients with Recurrent or Metastatic Nasopharyngeal Carcinoma Chia‑Hsun Hsieh1,2, Cheng‑Lung Hsu1, Cheng‑Hsu Wang3, Chaung‑Chi Liaw1, Jen‑Shi Chen1, Hsien‑Kun Chang1, Tsai‑Shen Yang1, John Wen‑Chen Chang1, Yung‑Chang Lin1, Chi‑Ting Liau1, Ngan‑Ming Tsang4, Joseph Tung‑Chieh Chang4, Shu‑Hang Ng5, Hung‑Ming Wang1 This prospective phase II clinical trial evaluated the ef‑ Background: At a Glance Commentary ficacy and toxicity of cisplatin, oral tegafur‑uracil, leu‑ covorin, and mitomycin C in patients with recurrent or Scientific background of the subject metastatic nasopharyngeal carcinoma. New chemotherapeutic agents and Methods: Patients with histologically proven non‑keratinizing or combinations are expected to improve the undifferentiated nasopharyngeal carcinoma were prospec‑ side effects and the response of conven‑ tively enrolled from April 2002 to June 2005. Cisplatin tional chemotherapy in recurrent/metastatic 50 mg/m2 on day 1, 22 and mitomycin C 6 mg/m2 on day nasopharyngeal carcinoma (NPC). Safety, 1 were administered. Oral tegafur‑uracil 300 mg/m2/day efficacy and convenience of use are all concerned for new design. and oral leucovorin 60 mg/day were given on day 1‑14 and day 22‑35, respectively. Each cycle was repeated every What this study adds to the field 6 weeks. Primary and secondary endpoints are response This prospective phase II trial evalu‑ rate and toxic profiles with survivals, respectively. ated the efficacy and toxicity of cisplatin, Results: Twenty‑two patients with the median age of 47 (35‑69) oral tegafur‑uracil, leucovorin, and mito‑ years were enrolled in the study. Sixteen (72.7%) patients mycin C in NPC. Results showed that this had undifferentiated nasopharyngeal carcinoma. The regi‑ regimen is acceptably effective and safe men was well‑tolerated by all patients with the exception to be performed in outpatient clinics. This of one patient (4.6%) who experienced grade IV anorexia, work provides an important information of and two patients (9.1%) who had grade IV vomiting. There new combination (PULM) to the treatment was no treatment‑related death. The overall response rate for mNPC patients. was 59.1%, including 3 (13.6%) complete remissions. The median duration of response was 15.9 months, the median time to tumor progression was 10.0 months, and the median overall survival was 16.0 months. Conclusion: This outpatient chemotherapy regimen is acceptably effective and toxic among patients with recur‑ rent or metastatic nasopharyngeal carcinoma. (Biomed J 2013;36:229-236) Key words: cisplatin, head and neck neoplasms, leucovorin, mitomycin C, nasopharyngeal cancer, tegafur‑uracil From the 1Division of Hematology‑Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan; 2Department of Chemical Engineering and Institute of Chemical and Materials Engineering, Chang Gung University, Taoyuan, Taiwan; 3Department of Diagnostic Radiology, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan; 4Department of Radiation Oncology, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan; 5Division of Hematology‑Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Keelung, Chang Gung University College of Medicine, Taoyuan, Taiwan Received: Jun. 6, 2012; Accepted: Aug. 30, 2012 Correspondence to: Dr. Hung‑Ming Wang, 5, Fusing St., Gueishan, Taoyuan 333, Taiwan (R.O.C.). Tel: 886‑3‑3281200 ext. 8825; Fax: 886‑3‑3286697; E‑mail: [email protected] DOI: 10.4103/2319‑4170.113375 230 Chia‑Hsun Hsieh, et al. PULM regimen in NPC asopharyngeal carcinoma (NPC) is uncommon in the METHODS NUnited States and Western Europe; however, is very prevalent in Southeast Asian countries, including Taiwan. Protocol of this prospective phase II clinical trial was The overall incidence of NPC is only around 0.7 cases per approved by the institutional review board of the Chang 100,000 population per year in the United States; however, Gung Memorial Hospital at Linkou and informed consent is as high as 15‑30 cases per 100,000 population per year in was obtained from all patients. From April 2002 to June Hong Kong.[1] According to the cancer registry of Taiwan, 2005, we enrolled patients aged 18 and 70 years NPC accounted for 2.02% of the cancer incidence with with histologically proven nonkeratinizing poorly‑differ‑ 1,558 incident cases in 2008. The crude incidence rates were entiated or undifferentiated nasopharyngeal≧ ≦carcinoma, 9.99 per 100,000 per year for men, and 3.47 per 100,000 as defined by the World Health Organization (WHO). per year for women.[2] Under the Fleming one stage design, the sample size was Before 2008, many phase II clinical studies of che‑ estimated to be 42 patients with alpha (0.05), power (0.90) motherapy for patients with recurrent or metastatic NPC and expected response rate of 69.5%.[26] All patients had demonstrated median response rates of approximately Eastern Cooperative Oncology Group (ECOG) perfor‑ 45% to 80%, with median survival ranging from 7.2 to mance status scores ranging from 0 to 2, and recurrent 15 months.[3‑7] These active chemotherapeutic agents com‑ or metastatic diseases that had not been treated by ra‑ prised of cisplatin, 5‑fluorouracil (5‑FU), doxorubicin, diotherapy or surgery with curative intent. Previously epirubicin, bleomycin, mitoxantrone, mitomycin C, taxanes, concurrent chemo‑radiotherapy regimens for local disease gemcitabine, cetuximab and sorafenib.[8‑16] Among all of the were allowed with the exception of oral Tegafur‑uracil combinations, cisplatin plus 5‑FU is still the most commonly or mitomycin C exposure. None of the patients enrolled used regimen for NPC, because no phase III studies have in this study had received chemotherapy or radiotherapy found any other regimen to be superior. However, evidence within 4 weeks of entry. All enrolled patients had at least showed that there is still a curative role for optimized che‑ one measurable recurrent or distant metastatic lesion. motherapy combinations in patients with complete remission A measurable lesion was defined as one measuring 20 mm and in long‑term survivors.[17] by conventional techniques or 10 mm by spiral comput‑ Tegafur‑uracil (UFT, UFUR, TTY Biopharm Co. Ltd, erized tomography scans in the longest dimension. Bone Taipei, Taiwan) is an oral preparation combining tega‑ lesions are included for response≧ evaluation in this trial fur (5‑fluorouracil prodrug) and uracil in a 1:4 ratio. This because bone is the most common site of metastases of chemotherapeutic agent has a low toxicity profile, is well NPC. Prostate cancer project criteria were utilized in this tolerated by most patients, can be easily combined with other trial for response evaluation of bone lesions.[27] Adequate chemotherapeutic agents, and is convenient to administer in bone marrow and organ function was defined as: (a) an outpatient settings.[18] In gastrointestinal, lung, and breast can‑ absolute neutrophil count 1,500/μL; (b) a platelet cers, Tegafur‑uracil is often used as an alternative to 5‑FU.[19‑22] count 100,000/μL; (c) a serum creatinine 1.5 times In addition, we previously reported that a Tegafur‑uracil‑based the upper limit of normal (ULN)≧ or 24‑hour creatinine chemotherapy regimen (cisplatin, Tegafur‑uracil, leucovorin; clearance≧ 60 ml/min; (d) total bilirubin ≦ 1.5 × ULN PUL) was effective and less toxic for patients with head and or 5.0 × ULN in patients with hepatic metastasis; neck squamous carcinoma (HNSCC).[23] Mitomycin C (M) and (e) serum≧ aspartate aminotransferase≦ and alanine is active in hypoxic circumstances and helps against tumor transaminase≦ 2.5 × ULN or 5.0 × ULN in patients cells in the G0 phase. In recent studies, tumor hypoxia is with hepatic metastasis. found to be common in NPC, and is associated with disease Exclusion≦ criteria consisted of≦ decompensated liver cir‑ progression and resistance to therapy.[24] Adding mitomycin C rhosis; clinically detectable peripheral neuropathy in Oxali‑ to a cisplatin‑based chemotherapy regimen may help to over‑ platin Specific Neurological Scale grade 2; active cardiac come resistance conferred by hypoxia and eradicate tumor disease within 6 months (e.g., angina, myocardial disease); cells, even those that are not in the cell cycle.[16] Since NPC active infection; history of another malignancy≧ with the appears to be highly sensitive to chemotherapy as well as exception of successfully treated cervical or skin carcinoma; radiotherapy,[25] the non‑overlapping toxicity profile of mito‑ pregnancy or breast‑feeding status; ongoing anticancer treat‑ mycin C, cisplatin, and oral fluoropyrimidines warrants such ment; documented hypersensitivity to any component of the a combination for NPC, especially for outpatient settings. study drugs; and intestinal obstruction or malabsorption that Therefore, we conducted this phase II trial to evaluate may preclude absorption of Tegafur‑uracil. the efficacy and toxicity of cisplatin, Tegafur‑uracil, leucovo‑ Eligible patients were treated with cisplatin, tega‑ rin, and mitomycin C (PULM) as an outpatient chemotherapy fur‑uracil (UFUR), leucovorin, and mitomycin C (PULM regimen for patients with recurrent or metastatic NPC. regimen). Cisplatin 50 mg/m2 was administered intrave‑ Biomed J Vol. 36 No. 5 September - October 2013 Chia‑Hsun Hsieh, et al. 231 PULM regimen in NPC nously in 500 ml of 0.9% normal saline or 5% dextrose TTP was defined as survival without disease progression in 0.9% normal saline over 3 hours on day 1 and day 22. or death from any cause. It was calculated from the first Oral Tegafur‑uracil 300 mg/m2/day with oral leucovorin day of PULM administration to the date of progression or 60 mg/day was given on day 1‑14 and day 22‑35. Mitomy‑ most recent follow‑up date.
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