635 Outpatient Weekly Chemotherapy in Patients with Nasopharyngeal Carcinoma and Distant Metastasis Jin-Ching Lin, M.D.1,2,3 Jian-Sheng Jan, M.D.1,2 Chen-Yi Hsu, M.D.4 1 Department of Radiation Oncology, Taichung Veterans General Hospital, Taichung, Taiwan. 2 School of Medicine, China Medical College, Taichung, Taiwan. 3 Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan. 4 Department of Otorhinolaryngology, Taichung Veterans General Hospital, Taichung, Taiwan. Presented at the 46th Annual Meeting of The Radiological Society of the Republic of China, Taipei, Taiwan, March 27–28, 1997. Supported by grants from Taichung Veterans General Hospital, Taiwan, Republic of China (TVGH857102). Address for reprints: Jin-Ching Lin, M.D., Department of Radiation Oncology, Taichung Veterans General Hospital, 160, Sec. 3, Taichung-Kang Road, Taichung, Taiwan. Received July 7, 1997; revisions received November 21, 1997, and February 9, 1998; accepted February 9, 1998. © 1998 American Cancer Society BACKGROUND. Distant metastasis is a more common pattern of failure than locoregional recurrence after adequate radiotherapy in patients with nasopharyngeal carcinoma (NPC). The objective of this Phase II study was to assess the efficacy and toxicity of weekly chemotherapy in NPC patients with distant metastasis. METHODS. Patients with a histologic diagnosis of NPC and documented distant metastasis were eligible, including those who 1) had metastatic disease at presentation; 2) had developed metastatic disease during or at any time after local radiotherapy; or 3) had developed progressive disease or recurrence of metastasis after prior chemotherapy. The weekly chemotherapy regimen was comprised of 5-fluorouracil (5-FU), 1250 mg/m2, plus cisplatin, 25 mg/m2, as a 24-hour continuous intravenous infusion via a subcutaneous implanted port, using an ambulatory pump in an outpatient setting for the first 19 patients. Because of the low incidence and reduced severity of toxicity, the dosage of chemotherapy was escalated to 5-FU, 1667 mg/m2, plus cisplatin, 33.3 mg/m2, for the subsequent 25 patients. RESULTS. Between October 1992 and June 1996, a total of 44 patients with metastatic NPC were studied. They were 36 males and 8 females with a median age of 48 years (range, 30 –72 years). Poorly differentiated epidermoid carcinoma or undifferentiated carcinoma were the major pathologic types. Twenty-six patients had single organ metastasis, whereas 18 patients had multiple organ involvement. Locoregional disease existed simultaneously in 16 patients. The majority of patients had received previous radiotherapy (33 patients) and chemotherapy (23 patients: 16 as concurrent therapy for localized disease, 6 as salvage therapy for metastatic disease, and 1 for a postradiation adjuvant purpose). Among 38 patients with measurable disease, 8 obtained a complete response (CR) (21.1%), 12 obtained a partial response (PR) (31.6%), 17 had stable disease (SD) (44.7%), and 1 had progressive disease (2.6%). The median duration of CR, PR, and SD were 6.5 months, (range, 2–12 months), 5.5 months (range, 2–9 months), and 2.5 months (range, 1– 6 months), respectively. Toxicity was found to be very mild. Only one patient developed a World Health Organization (WHO) Grade 1 mucositis. No visible alopecia and no treatment-related deaths occurred. WHO Grade 3– 4 hematologic toxicities occurred in 1.0% of patients for leukopenia, 4.1% for anemia, and 2.9% for thrombocytopenia. CONCLUSIONS. Data from the current study indicate that 24-hour weekly infusion of 5-FU plus cisplatin has moderate activity but very low toxicity for NPC patients with distant metastasis. Further study is necessary to find more effective therapy. Cancer 1998;83:635– 40. © 1998 American Cancer Society. KEYWORDS: nasopharyngeal carcinoma, distant metastasis, weekly, chemotherapy. N asopharyngeal carcinoma (NPC) is unique to the head and neck region. It has several different characteristics among head and neck malignancies. It is a geographically endemic, Epstein-Barr virus- 636 CANCER August 15, 1998 / Volume 83 / Number 4 associated carcinoma of epidermoid origin and poorly differentiated or undifferentiated pathology with a higher incidence of neck lymph node metastasis, greater radiosensitivity, and greater chemosensitivity. Treatment primarily is by radiation with more distant failure and a lower rate of second malignant tumor occurrence. Radiotherapy is the mainstay of treatment of NPC, primarily because of anatomic constraints and a high degree of radiosensitivity. Although early stage NPC is highly radiocurable, the treatment result of locoregionally advanced NPC is disappointing. Unfortunately, the majority of NPC patients present with late stage disease. Lee et al. reported that only 9% of the 5037 cases collected from the Queen Elizabeth Hospital in Hong Kong had their tumor confined to the nasopharynx without clinically involved lymph nodes.1 The major pattern of failure after adequate radiotherapy is distant metastasis.1–5 Distant metastasis has been shown to be the most important determinant of survival.5– 8 Although a small percentage of patients with locoregionally recurrent NPC can be salvaged, nearly all those with distant metastasis die of the disease in a rapidly progressive course. How to develop effective therapy for patients with distant metastasis is a great challenge for oncologists. Weekly chemotherapy is a new schedule of drug delivery that has become more popular in the treatment of various cancers in recent years. To date, there is little information regarding the role of systemic chemotherapy in the management of patients with metastatic NPC. In October 1992, a prospective Phase II study was initiated to evaluate the compliance, response, and toxicities of outpatient, weekly, 24-hour continuous infusion chemotherapy for NPC patients with distant metastasis. PATIENTS AND METHODS Patients with metastatic NPC were eligible, including those who 1) had metastatic disease at presentation; 2) had developed metastatic disease during or at any time after local radiotherapy; or 3) had developed progressive disease or recurrence of metastasis after prior chemotherapy. Other eligibility criteria were 1) histologic diagnosis of NPC; 2) Karnofsky performance status . 50%; 3) pretreatment leukocyte count . 3000/mm3 and a platelet count . 100,000/mm3 (except for patients with bone marrow metastases); 4) a serum creatinine level , 2.0 mg/dL; 5) normal liver function with total bilirubin , 2.5 mg/dL (unless attributable to hepatic metastasis); 6) minimal 3-week interval from prior chemotherapy, radiotherapy, or surgery; and (7) obtaining informed consent. Treatment Schedule The weekly chemotherapy was comprised of cisplatin, 25 mg/m2, plus 5-fluorouracil (5-FU), 1250 mg/m2, mixed in 100 –150 mL of normal saline given by continuous intravenous (i.v.) infusion for 24 hours via a subcutaneous implanted port, using an ambulatory pump in an outpatient setting for the first 19 patients. Because of the low incidence and reduced severity of toxicity, the dosage was escalated to cisplatin, 33.3 mg/m2, plus 5-FU, 1667 mg/m2, for the remaining 25 cases. A total of 24 doses was planned. Chemotherapy was administered until documentation of disease progression, patient refusal, or delivery of 24 cycles. The weekly chemotherapy was delayed if World Health Organization Grade 3– 4 toxicity developed, and resumed after recovery. Two patients received a 20% dose reduction because of one patient developing bone marrow metastasis with pancytopenia and the other having a past history of chemotherapy-induced Grade 4 bone marrow toxicity. This dose reduction was not defined prospectively. Evaluation of Treatment Objective responses and toxicity were assessed according to WHO criteria.9 Response evaluation was planned after every 6 – 8 weeks. The duration of complete response (CR), partial response (PR), and stable disease (SD) was calculated from the day when these responses were documented. RESULTS Patient Characteristics and Previous Treatment From October 1992 through June 1996, a total of 44 NPC patients with distant metastasis (14 initial M1 and 30 initial M0 after a disease free interval ranging from 3– 80 months; median, 12 months) were entered. Patient characteristics are shown in Table 1. All patients except four were symptomatic. Approximately half the patients (47.7%) had metastasis documented pathologically by either resection, biopsy, or fine-needle needle aspiration of the metastatic lesion. Before weekly chemotherapy, a detailed survey of possible disease sites was performed. Single organ metastasis was noted in 26 patients, and 18 patients had multiple organ metastasis. At the time of initiation of weekly chemotherapy, locoregional disease existed simultaneously with distant metatasis in 16 patients, either recurrent or as the initial presentation. Thirty-three patients had received previous radiotherapy, and 23 patients had been exposed to various forms of chemotherapy before being entered into this trial. The preceding radiation therapy was comprised Weekly Chemotherapy for Metastatic NPC/Lin et al. TABLE 1 Patient Characteristics Characteristic Gender Male/female Age (yrs) Range Median Prechemotherapy Karnofsky performance status 90% 80% 70% 60% 50% Pathology WHO type 1 WHO type 2 WHO type 3 Previous radiotherapy Yes No Previous chemotherapy Yes No Metastasis proven by biopsy Yes No Associated with locoregional disease Yes No 637 Patient Compliance and Actual Dose Delivery No. % 36/8 30–72 48 4 9 14 9 8 9.1 20.5 31.8 20.5 18.2 1 32 11 2.3 72.7 25.0 33 11 75.0 25.0 23 21 52.3 47.7 21 23 47.7 52.3 16 28 36.4 63.6 WHO: World Health Organization. of curative irradiation (18 patients), curative concurrent chemoradiotherapy (13 patients), and palliative locoregional irradiation (2 patients). Reirradiation was given to four patients who developed primary and/or neck recurrence. Palliative radiotherapy for painful bony metastasis was performed on six patients. Previous chemotherapy was comprised of concurrent chemotherapy during curative locoregional radiotherapy for 13 patients, and during the second irradiation for 3 recurrent patients with a regimen of cisplatin, 75– 80 mg/m2, on Day 1 plus 5-FU, 400 mg/m2/day, on Days 1– 4, continuous i.v. infusion, monthly for 2 cycles; a different schedule of systemic chemotherapy for metastatic disease for 6 patients was comprised of a regimen of cisplatin, 100 mg/m2, on Day 1 plus 5-FU, 1000 mg/m2/day, on Days 1–5, continuous i.v. infusion, every 3– 4 weeks (1 patient also received neoadjuvant chemotherapy comprised of bleomycin, epirubicin, and cisplatin before his curative radiotherapy); in 1 patient postradiation adjuvant chemotherapy was a regimen of cisplatin, 50 mg/m2, on Day 1 plus 5-FU, 500 mg/m2/day, on Days 1–5, continuous i.v. infusion, monthly for 2 cycles. Eighteen of 44 patients completed the planned 24 cycles of weekly chemotherapy. The causes of premature interruption were disease progression (14 patients) and patient refusal (12 patients). The reasons for patient refusal were the psychologic stress of a more frequent drug delivery schedule (eight patients), SD (three patients), and because one patient was a single elderly veteran without any family support. Although the original design was only 24 cycles of chemotherapy, we continued to treat patients if they so requested, or when the tumor recurred after treatment withdrawal. As of March 1997, there were two patients still receiving treatment. By that time a total of 920 cycles had been delivered to 44 patients, with a median of 19 doses (range, 2– 48 doses). Tumor Response and Patient Survival Of 44 patients entered, 38 had measurable lesions for response evaluation. We observed 8 CR (21.1%) and 12 PR (31.6%) for an overall response rate of 52.7%. Seventeen patients had SD (44.7%), and 1 patient had progressive disease. The median durations of CR, PR, and SD were 6.5 months (range, 2–12 months), 5.5 months (range, 2–9 months), and 2.5 months (range, 1– 6 months), respectively. No patients were lost to follow-up. By May 1997, all patients had disease progression, and only four patients were still alive with active disease. The median survival for the whole cohort was 9 months (range, 2–25 months); the 1-year survival rate was 40%. Toxicity Acute toxicity was very mild and well tolerated. Some patients experienced mild anorexia and weakness during the chemotherapy. Nausea and emesis occurred in only 6 of the 44 patients during treatment, but usually was mild (less than Grade 2). No patients developed mucositis except for one who was graded as only Grade 1. Alopecia was very mild and usually invisible. Loss of body weight seldom was noted and no diarrhea occurred. Hematologic toxicity was infrequent and mild. WHO Grade 3– 4 toxicities occurred in 1.0% of patients for leukopenia, 2.9% of patients for thrombocytopenia, and 4.1% of patients for anemia. They recovered soon after transient discontinuation of the chemotherapy infusion. DISCUSSION NPC is a common cancer in Taiwan. Although early stage NPC is highly radiocurable, the cure rate of radiotherapy alone for advanced NPC is low. The pat- 638 CANCER August 15, 1998 / Volume 83 / Number 4 TABLE 2 Chemotherapy for Metastatic/Recurrent Nasopharyngeal Carcinoma % outcome for MET/REC Ref. Total cases No. of MET/REC/LA Regimen CR PR RR 14 19 20 21 22 23 111 24 49 44 21 70 38/6/67 24/0/0 41/8/0 9/14/21 19/2/0 31/39/0 24 25 26 27 28 108 24 35 42 39 44 22/86/0 21/3/0 15/6/14 17/5/20 15/24/0 44/0/0 BEC Paclitaxel PBF FEBP Low dose protracted F Various single agent Combined Mitoxantrone PF PFL Weekly PFL PBM, PF, PFL Weekly PF 20 0 19 35 10 7.5 23.3 5 14 13.3 23.5 20.5 21.1 25 26 60 45 15 17.5 46.7 20 42 67.6 47.1 43.5 31.6 45 26 79 80 25 25 70 25 66 80a 70.6a 64 52.7b MET: metastatic; Rec: recurrent; LA: locally advanced but nonmetastatic; CR: complete response; PR: partial response; RR: overall response rate; P: cisplatin; B: bleomycin; F: 5-fluorouracil; E: epirubicin; C: cisplatin; L: leucovorin; M: methotrexate. a The response rate was calculated for distant metastasis only. b Current study. terns of failure in the past have been high rates of both local recurrence and distant metastasis. Because of recent advances in radiation oncology such as megavoltage radiation, improved immobilization and simulation systems, and precise localization of the tumor extension by computed tomography scan, the failure pattern predominantly has changed to distant metastasis.1–5 Distant metastasis has been shown to be the most important determinant of patient survival.5– 8 How to overcome the problem of distant metastasis remains an urgent issue. For symptomatic patients with distant metastasis, systemic chemotherapy usually is recommended. Although NPC usually is regarded as a chemosensitive tumor, the cure rate for metastatic NPC is nearly zero, with a 2-year survival rate , 10%.10 –13 The median survival is 3– 6 months for untreated patients and 8 –12 months for those treated by chemotherapy. The reports focusing on NPC patients with distant metastasis are very rare in the literature. The majority of chemotherapy protocols in this setting may originate from the vast experiences of neoadjuvant chemotherapy for previously untreated patients with advanced but nonmetastatic NPC. Cisplatin-based combination chemotherapy, such as BEC (bleomycin, epirubicin, and cisplatin) or PF (cisplatin and 5-FU) are the most active regimens for NPC in the literature. When the BEC regimen was used as neoadjuvant chemotherapy for patients with non- metastatic NPC, very high overall response rates (range, 91–98%) and CR rates (range, 44 – 62%) were reported.14 –16 Comparably high overall response rates (range, 81–93.2%) but lower CR rates (range, 19 –20.5%) were observed when PF was given.17,18 Although highly chemoresponsive for previously untreated NPC, the toxicity of cisplatin-based regimens is moderate and their contribution to survival benefit remains controversial. Because of the infrequent occurrence of NPC in the U.S. and other developed countries, the response and survival outcome of NPC patients with distant metastasis who receive systemic chemotherapy usually have been reported as part of the collective database of studies of patients with locoregional recurrence or previously untreated, advanced stage disease. To the best of the our knowledge, so far there have been no articles published that discuss metastatic NPC alone, with the exception of a Phase II study from Singapore in the form of a meeting abstract.19 We reviewed all studies in the literature containing at least 15 patients with distant metastasis. The findings are summarized in Table 2.14,19 –28 The response rate ranged from 25– 80% with a CR rate of between 0 –35%. Based on a thorough review of the literature, we believe there is no existing highly effective protocol for the treatment of metastatic NPC. The CR usually is , 20%, the duration of response is brief, the Weekly Chemotherapy for Metastatic NPC/Lin et al. median survival is approximately 1 year, and the toxicity usually is higher if a more aggressive combination chemotherapy delivery is attempted. In our previous experience dealing with metastatic NPC patients receiving monthly PF chemotherapy, we noticed high rates of toxicity and poor patient compliance. Some patients refused further chemotherapy and dropped out of the study after one to two cycles. We accordingly have changed our management, and tried to develop a less toxic therapy. We divided the original PF regimen into three to four weekly doses. The dose intensity was the same as in a monthly schedule. From our data of weekly 24-hour infusional PF chemotherapy, we found a comparable response rate but a marked reduction in acute toxicity. The outpatient nature of this treatment and no noted occurrence of alopecia allowed normal social activity. 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