Japanese Journal of Clinical Oncology 31:589-595 (2001)
© 2001 Foundation for Promotion of Cancer Research
Therapeutic Results of Alternating Chemoradiotherapy for Nasopharyngeal Cancer using Cisplatin and 5-Fluorouracil: Its Usefulness and Controversial Points
Department of Radiation Oncology, Aichi Cancer Center Hospital, Nagoya, Japan
 |
ABSTRACT |
|---|
 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Background: The present study was conducted to evaluate the therapeutic results of alternating chemoradiotherapy for locally advanced nasopharyngeal cancer (NPC).
Methods: The subjects consisted of six patients with stage III nasopharyngeal cancer and 26 patients with stage IV nasopharyngeal cancer. Using 6 MV photons, radiotherapy was performed at an exposure of 1.8–2.0 Gy five times per week. That is, a total absorbed dose of 36–40 Gy was irradiated between the base of the skull and supraclavicular fossa. After decreasing the irradiation field, an absorbed dose of 26–30 Gy was additionally given thereafter. One course of chemotherapy consisted of the administration of 5-fluorouracil (5-FU) at a dose of 700 mg/m2/24 h for 5 days (days 1–5) and cisplatin (CDDP) at a dose of 50 mg/m2/24 h for 2 days (days 6–7) and a total of 2–3 courses of chemotherapy were performed. During the alternating chemoradiotherapy, chemotherapy was performed initially and 3–5 days after completing the chemotherapy, radiotherapy was performed for 3–4 weeks. Thereafter, chemotherapy and radiotherapy were performed alternately.
Results: The scheduled courses of alternating chemoradiotherapy were completed in 30 (94%) of 32 patients. Although one patient developed shock induced by metal allergy to CDDP, no severe adverse effects were noted in any other patients. In these 32 patients, the overall 5-year survival rate was 75% (95% confidence interval: 60–90%) and the progression-free survival rate was 63% (95% CI: 46–89%).
Conclusions: This method of alternating chemoradiotherapy yielded higher or at least similar survival rates and lower toxicities than concurrent chemoradiotherapy and is worth trying in a multi-institutional study.
|
INTRODUCTION |
|---|
|
TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Although the incidence of nasopharyngeal cancer is high in the southern part of China (1,2), its incidence in Japan is rather low and is similar to that in Western countries (3). Owing to its anatomical characteristics, the surgical treatment of nasopharyngeal cancer is very difficult to perform. In addition, most cases of nasopharyngeal cancer are histologically classified as undifferentiated carcinoma with relatively high radiosensitivity. Therefore, radiotherapy is the first choice of treatment modality for nasopharyngeal cancer (4–8). However, although nasopharyngeal cancer is more sensitive than other head and neck cancers to radiotherapy, the overall 5-year survival rate reported in a large series was 41% (9). Therefore, various combinations of radiotherapy and chemotherapy, such as concurrent chemoradiotherapy (10–12), neoadjuvant therapy (13–17), adjuvant therapy (18,19) and alternating therapy (20), have been attempted.
Although many phase II studies previously reported useful combinations of radiotherapy and chemotherapy (10,18,20–23), only four randomized phase III studies evaluated the anti-tumor effects of chemoradiotherapy in comparison with those of radiotherapy alone (24–27). Two of these four studies reported that the progression-free survival (PFS) rate was significantly more satisfactory in patients treated with chemoradiotherapy than in those treated with radiotherapy alone (24,27). In particular, very satisfactory therapeutic results were obtained in the Intergroup 0099, in which cisplatin (CDDP) was administered concurrently with radiotherapy and the combination of CDDP and 5-fluorouracil (5-FU) was subsequently administered after radiotherapy (24). Therefore, the above combination of chemotherapy and radiotherapy may become a standard treatment modality for nasopharyngeal cancer in the future.
In 1987, we initiated alternating chemoradiotherapy using CDDP and 5-FU. Although the number of subjects was limited, our previous non-randomized study showed therapeutic results similar to those of chemoradiotherapy demonstrated by the Intergroup 0099 trial. In the present study, we evaluated the therapeutic results of alternating chemoradiotherapy, together with its usefulness and controversial points.
|
PATIENTS AND METHODS |
|---|
|
TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Between 1987 and 1996, patients with nasopharyngeal cancer who met all the following criteria were treated by alternating chemoradiotherapy: (1) those with nasopharyngeal cancer histologically classified as types I–III according to the World Health Organization (WHO) classification; (2) those with stage III or IV nasopharyngeal cancer without distant metastasis according to the 1987 TNM classification (28); (3) those who showed a performance status (PS) between 0 and 2 according to the Eastern Cooperative Oncology Group (ECOG) classification; (4) those between 15 and 70 years of age; (5) those with sufficient bone marrow function (WBC count >3500/mm2, platelet count >100 000/mm2); (6) those without severe hepatic, renal, cardiac and pulmonary dysfunctions, as well as showing 24-h creatinine clearance above 60 ml/min; (7) those with untreated nasopharyngeal cancer; (8) those without active double cancers at the beginning of this alternating therapy; and (9) those who gave written informed consent.
The progression range of the primary lesion in the nasopharynx was evaluated by MRI and pharyngeal fiberoptic endoscopy. Metastasis to the cervical lymph nodes was evaluated by CT, MRI and palpation. The presence or absence of distant metastasis was investigated by chest X-ray, liver ultrasonography or CT and bone scintigraphy.
Methods
Fig. 1 shows the method of combining chemotherapy with radiotherapy. Briefly, chemotherapy was performed initially and 3–5 days after completing the first course of the chemotherapy, radiotherapy was performed for 3–4 weeks. Thereafter, chemotherapy and radiotherapy were performed alternately. Between June 1987 and June 1990, two courses of chemotherapy were performed in seven patients. However, distant metastasis was detected in two of these seven patients. Therefore, three courses of chemotherapy were performed thereafter in principle.
|
Using 6 MV photons accelerated by a linear accelerator, radiotherapy was performed at an exposure of 1.8–2.0 Gy five times per week. The irradiation field was limited between the nasopharynx and the basal skull and the middle cervical lymph nodes were irradiated at a total absorbed dose of 36–40 Gy using the bilateral opposing portal irradiation method, whereas the area between the lower cervical part and the supraclavicular fossa was irradiated at the same absorbed dose of 36–40 Gy using the anterior single irradiation method. The irradiation field was decreased thereafter and conformal radiation therapy using 6 MV photons was performed by additionally irradiating the nasopharynx at an absorbed dose of 26–30 Gy using the rotation technique. The irradiation field was further decreased and 10 Gy of 6 MV photons were additionally irradiated in patients with T4 cases who showed apparent tumor cell infiltration into the basal skull. Using the anteroposterior portal irradiation method, 26–30 Gy of 6 MV photons or electron beam were additionally irradiated only to the cervical lymph nodes, in which tumor metastasis was detected at the initial examination.
One course of chemotherapy consisted of continuous i.v. administration of 5-FU at a dose of 700 mg/m2/24 h for 5 days (days 1–5) and CDDP at a dose of 50 mg/m2/24 h for 2 days (days 6–7). When CDDP was administered, the volume of drip infusion was 4 l/day and the minimal urine volume was maintained at 2 l/day for 1 week after CDDP administration. Since 1992, antiemetics such as ondansetron hydrochloride and granisetron hydrochloride have been used before CDDP administration.
Chemotherapy was performed at 4-week intervals in principle. However, chemotherapy was not performed when serum creatinine levels were >1.5 mg/dl on the scheduled date of drug administration. Moreover, when a WBC count <3000/mm2 or a platelet count <100 000/mm2 was obtained at the scheduled date of drug administration, chemotherapy was postponed and radiotherapy was performed instead. When hematological data obtained 2 weeks after radiotherapy did not meet the inclusion criteria (WBC count >3000/mm2 and platelet count >100 000/mm2), the performance of chemotherapy was abandoned. When the WBC count was decreased to <1000/mm2 or the platelet count was decreased to <25 000/mm2 after chemotherapy, the doses of 5-FU and CDDP were decreased by 25% at the next administration. Moreover, the dose of the next CDDP administration alone was decreased by 25% when serum creatinine levels >1.5 mg/dl were obtained.
Patient Assessments
According to the WHO criteria (29), the toxicity of this alternating chemoradiotherapy was evaluated by assessing changes in WBC counts, neutrophil counts, platelet counts, hemoglobin levels, liver function, renal function, oral mucositis and nausea and vomiting. During the treatment period, complete cell counts were measured at least twice per week and hematological and biochemical examinations were performed once per week.
According to the WHO criteria (29), the anti-tumor effects of this alternating chemoradiotherapy were evaluated based on the results of pharyngeal fiber-optic endoscopy and MRI performed within 1 month after the completion of the treatment. The therapeutic values of this treatment were also evaluated in the cervical lymph nodes based on the results of MRI, CT or palpation. The frequency of post-treatment examinations at the outpatient clinic was established once every 4 weeks between the completion of the treatment and the first post-treatment year, once every 8 weeks between the second and third post-treatment years and once every 3 months after the third post-treatment year. Pharyngeal fiber-optic endoscopy was performed at every visit to the outpatient clinic, whereas MRI was performed once every 3 months between the completion of the treatment and the second post-treatment years and once every 6 months thereafter. Moreover, chest X-ray, liver ultrasonography and CT and bone scintigraphy were performed once every 6 months.
Progression-free survival (PFS) rates and overall survival (OS) rates were calculated by the Kaplan–Meier method (30). The survival period was measured starting from the day where the alternating chemoradiotherapy was initiated. PFS rates were calculated based on the day of events when the progression of the tumor or the presence of a new lesion was confirmed or when patients died of other diseases despite the control of the tumor.
|
RESULTS |
|---|
|
TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Between June 1987 and December 1996, 35 patients with nasopharyngeal cancer who met the inclusion criteria described above were registered for this study. However, three of them were excluded owing to complications due to psychosis in one patient and renal insufficiency in another. The last patient was excluded from the study because radiotherapy had already been performed in the nasopharynx to treat prior maxillary sinus cancer and sufficient irradiation could not be performed in the nasopharynx.
The ages of these 32 patients (22 males and 10 females) ranged between 21 and 69 years (median: 51 years). PS was evaluated to be 0 in five patients, 1 in 18 patients and 2 in nine patients. Histology revealed that three cases of nasopharyngeal cancer were WHO type I, four were type II and 25 were type III. The TNM classification revealed that stage IV cancer accounted for the majority of all cases of nasopharyngeal cancer evaluated in this study (six stage III cancer vs 26 stage IV cancer). Using these 32 patients, the frequency of adverse effects, anti-tumor effects and survival rates were evaluated after alternating chemoradiotherapy. Table 1 gives the details of the subjects.
|
The total dose ranged between 44 and 76.8 Gy (median: 64.8 Gy) in the nasopharynx and between 55 and 72 Gy (median: 63 Gy) in the metastatic cervical lymph nodes. The nasopharynx was irradiated at a total dose of 44 Gy in patients who complained of severe mucositis and refused to receive further irradiation. The percentage of patients who received within 10% of the prescribed radiation dose to the nasopharynx and the metastatic cervical lymph nodes was 92 and 85%, respectively. The total duration of radiotherapy ranged from 44 to 100 days (median: 74.5 days). Although chemotherapy was discontinued in one patient during the first course, two courses of chemotherapy were performed in five patients and three courses of chemotherapy were performed in 26 patients. The total CDDP dose ranged from 10 to 300 mg/m2 (median: 280 mg/m2) and the total 5-FU dose from 3500 to 10 500 mg/m2 (median: 10 500 mg/m2). The percentage of patients who received within 10% of prescribed chemotherapy dose was 85%. The total duration of alternating chemoradiotherapy ranged between 55 and 139 days (median: 91.5 days). The post-treatment courses of these 32 patients were followed in detail.
Toxicity
The scheduled courses of alternating chemoradiotherapy were completed in 30 (94%) of 32 patients. The treatment was discontinued in one patient because both acute renal insufficiency and pulmonary edema occurred within a few hours after CDDP administration, resulting in a state of shock probably caused by an allergic reaction to platinum. However, the symptoms were relieved after management by artificial respiration and hemodialysis. Therefore, radiotherapy alone was performed in this patient thereafter. The third course of chemotherapy was discontinued in another patient because of persistent gastrointestinal symptoms.
Major adverse effects above grade 3 consisted of six cases of leukocytopenia and nine cases of vomiting. However, renal toxicity was below grade 1 in 31 patients except for one patient who was in a state of shock caused by grade IV renal toxicity. Table 2 shows the details of toxicity of this alternating chemoradiotherapy.
|
Anti-tumor Effects, Site of Initial Tumor Recurrence and Survival Rates
The response of the primary lesion in the nasopharynx to this alternating chemoradiotherapy was evaluated as complete response (CR) in 31 patients and partial response (PR) in one patient, whereas the response of the metastatic lesion in the cervical lymph nodes to the treatment was evaluated as CR in 28 patients and PR in four patients. One patient with nasopharyngeal cancer showed PR even after irradiation at a full dose of 70.4 Gy. Although the tumor mass was reduced thereafter, local progression was detected 18 months later. Because the metastatic lesion in the cervical lymph nodes decreased in four patients who showed PR, cervical lymph node dissection was not performed in any of these patients.
Distant metastases were detected between the 9–36 months post-treatment (median: 18 months) in five patients. In addition, recurrent tumors were detected in the nasopharynx between the 9–31 months post-treatment (median: 14 months) in five patients and a recurrent tumor in the cervical lymph nodes was detected in one patient 36 months post-treatment. Excluding the one patient who was in a state of shock after CDDP administration, alternating chemoradiotherapy using CDDP and 5-FU was performed again in six patients with localized tumor recurrence, while chemotherapy alone was performed in five patients with distant metastases of nasopharyngeal cancer using CDDP and 5-FU.
As of June 2001, although 42 months had passed after the second alternating chemoradiotherapy, one patient with recurrent nasopharyngeal cancer is still alive without any difficulty because the cancer is well controlled by the treatment. However, the remaining nine died of recurrent cancer. At present, 23 of 32 patients are alive and 21 of these 23 remain free of cancer. The post-treatment courses of these surviving patients were followed for 53–172 months (median: 70 months). Fig. 2 shows the PFS and OS rates (5-year PFS and OS rates were 63 ± 17 and 75 ± 15%, respectively).
|
Factors Involved in Local Control and Distant Metastasis of Nasopharyngeal Cancer (Table 3)
As factors possibly involved in local control of nasopharyngeal cancer, the total dose, total duration of radiotherapy, frequency of chemotherapy and tumor stage (T factor) were evaluated. However, none of them were significantly involved in local control of the tumor. In addition, when frequency of chemotherapy and the tumor stage (N factor) were evaluated as factors possibly involved in distant metastasis of nasopharyngeal cancer, N3 lymph node metastasis was found to be a factor significantly involved in distant metastasis of nasopharyngeal cancer.
|
|
DISCUSSION |
|---|
|
TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
As described initially, four previous randomized controlled studies evaluated the therapeutic values of combinations of radiotherapy and chemotherapy for nasopharyngeal cancer in comparison with those of radiotherapy alone (24–27). CDDP was commonly used in combination in four studies: 5-FU was used in two studies, epirubicin and bleomycin in one study and epirubicin one study. Anti-tumor agents were administered before radiotherapy (neoadjuvant therapy) in two studies, before and after radiotherapy (neoadjuvant and adjuvant therapies) in one study, simultaneously with radiotherapy (concurrent therapy) and after radiotherapy (adjuvant therapies) in one study. Two of these four studies reported that the PFS rate was significantly more satisfactory in patients treated with chemoradiotherapy than in those treated with radiotherapy alone. However, only the Intergroup 0099 trial in the USA showed a significantly higher OS rate. During this trial, 100 mg/m2 of CDDP were initially administered three times at 3-week intervals simultaneously with radiotherapy. Subsequently, the combination of 80 mg/m2 of CDDP and 1 g/m2/day of 5-FU by 96-h infusion was administered three times at 4-week intervals after the completion of radiotherapy. As a result, 3-year PFS rates were 69% in patients treated with chemoradiotherapy and 24% in those treated with radiotherapy alone. In addition, the 3-year OS rates were 78% in those treated with chemoradiotherapy and 47% in those treated with radiotherapy alone, demonstrating that the therapeutic results of chemoradiotherapy were superior to those of radiotherapy alone. These findings suggest that the therapeutic results of concurrent chemoradiotherapy may be superior to those of neoadjuvant therapy, in which chemotherapy is performed before radiotherapy, probably because the preceding chemotherapy induces an accelerated repopulation of cancer cells and reduces the therapeutic value of subsequent radiotherapy, resulting in decreased therapeutic results in neoadjuvant therapy (31,32).
Theoretically, the combination of concurrent radiotherapy and chemotherapy shows the highest anti-tumor effects. However, considering the impairment of normal tissues, combination therapy that increases the therapeutic gain factor is expected in the clinical setting.
CDDP-induced nephrotoxicity and gastrointestinal symptoms and 5-FU-induced mucositis are observed as the major toxicities of chemotherapy. In particular, markedly severe mucositis was reported to be induced when 5-FU was administered simultaneously with radiotherapy (33), which frequently resulted in the discontinuation of radiotherapy.
In the present study, concurrent administration of 5-FU was considered to be difficult in patients with nasopharyngeal cancer owing to the wide field of irradiation during radiotherapy. Therefore, we used alternating chemoradiotherapy. The results of this study showed that the severity of mucositis was acceptable and that the scheduled courses of chemoradiotherapy could be completed in 30 (94%) of 32 patients. In addition, although stage IV cancer accounted for ~80% of all cases of nasopharyngeal cancer evaluated in this study, satisfactory 5-year OS and 5-year PFS rates were obtained (75 and 63%, respectively). Compared with the Intergroup 0099 trial (24), our method was characterized by a decreased total dose of CDDP (540 mg/m2 in the Intergroup 0099 trial vs 300 mg/m2 in our method), a shorter treatment period (130 days in the Intergroup 0099 trial vs 91.5 days in our method) and a higher treatment completion rate (55%, 43 of 78 cases in the Intergroup 0099 trial vs 94%, 30 of 32 cases in our method).
Although there was no significant difference, a higher frequency of local tumor recurrence in patients who received radiotherapy for more than 75 days [more than 75 days 27% (4/15) vs less than 74 days 6% (1/16)] was one of the controversial points of this alternating chemoradiotherapy. Therefore, therapeutic tactics were changed as shown in Fig. 3, and phase II studies, in which the duration of radiotherapy was shortened and the dose of 5-FU was increased from 3500 mg/m2/120 h to 4000 mg/m2/120 h, were initiated in four institutions.
|
In June 2001, alternating chemoradiotherapy in 35 patients was completed. The post-treatment courses of these patients were followed for 6–48 months (median: 20 months). Although the duration of follow-up studies was limited, the scheduled courses of alternating chemoradiotherapy were completed in 32 (91%) of 35 patients and the 2-year OS and PFS rates were very satisfactory (94 ± 11 and 83 ± 17%, respectively). Therefore, attention was focused on the future therapeutic results of this alternating chemoradiotherapy.
Merlano et al. (34) reported the results of a large-scale randomized controlled study evaluating the therapeutic results of alternating chemoradiotherapy for advanced cancers localized in the cephalic and cervical regions in comparison with those of radiotherapy alone. Although the exposure was limited to 60 Gy in patients treated with alternating chemoradiotherapy and to 70 Gy in those treated with radiotherapy alone, the anti-tumor effects of alternating chemoradiotherapy were significantly greater than those of radiotherapy alone. Moreover, the survival rate was significantly higher in patients treated with alternating chemoradiotherapy than in those treated with radiotherapy alone. However, there were no differences in the severity of adverse effects, particularly the severity of mucositis, between patients treated with alternating chemoradiotherapy and radiotherapy alone. Therefore, they concluded that alternating chemoradiotherapy was a superior treatment modality for nasopharyngeal cancer owing to its greater anti-tumor effects and lower frequency of adverse effects.
Currently, most clinical trials of radiotherapy and chemotherapy for various cancers are evaluating the therapeutic values of concurrent combination therapy. However, normal tissue impairment induced by concurrent chemoradiotherapy sometimes becomes a great problem. Moreover, a decreased dose of chemotherapy and radiotherapy may result in a decreased therapeutic value, although the frequency of normal tissue impairment is decreased. Compared with concurrent chemoradiotherapy, sufficient doses of anti-tumor agents and radiation can be administered during alternating chemoradiotherapy, because alternating chemoradiotherapy hardly injures the normal tissue. Therefore, alternating chemoradiotherapy would be a useful treatment modality when normal tissue impairment during the treatment is particularly problematic. Because the frequency of distant metastasis is higher in patients with nasopharyngeal cancer, sufficient chemotherapy is required to control the primary and metastatic lesions. Moreover, owing to the wide field of irradiation, the concurrent administration of 5-FU is difficult during radiotherapy for nasopharyngeal cancer. Therefore, alternating chemoradiotherapy is considered a treatment modality worth trying for the treatment of nasopharyngeal cancer.
|
FOOTNOTES |
|---|
+ For reprints and all correspondence: Nobukazu Fuwa, Department of Radiation Oncology, Aichi Cancer Center Hospital, 1–1 Kanokoden, Chikusa-ku, Nagoya, Japan. E-mail: nfuwa@aichi-cc.jp
|
REFERENCES |
|---|
|
TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
1 Ho JHC. An epidemiological and clinical study of nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 1978;4:183–97.
2 Wang DC, Cai WM, Hu VC. Long term survival of 1035 cases of nasopharyngeal carcinoma. Cancer 1988;61:2328–41.
3 Sanada K, Kimura S, Fuhara T. In: Cancer Incidence in Five Continents, Vol. VII. Parkin DM, Whelan SL, Ferlay J, Raymond L, Young J, editors. IARC Scientific Publications No. 143. Lyon: IARC 1997;382–405.
4 Hoppe RT, Goffinet DR, Bagshaw MA. Carcinoma of the nasopharynx. Eighteen years experience with megavoltage radiation therapy. Cancer 1976;37:2605–12.[Web of Science][Medline]
5 Marcial VA, Hanley JA, Chang C, Davis LW, Moscol JA. Spirit-course radiation therapy of carcinoma of the nasopharynx: results of a national collaborative clinical trial of the Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys 1980;6:409–14.[Web of Science][Medline]
6 Mesic JB, Fletcher GH, Goepfert H. Megavoltage irradiation of epithelial tumors of the nasopharynx. Int J Radiat Oncol Biol Phys 1981;7:447–53.[Web of Science][Medline]
7 Perez CA, Ackerman LV, Mill WB, Ogura JH, Powers WE. Cancer of the nasopharynx. Factors influencing prognosis. Cancer 1969;24:1–17.[Web of Science][Medline]
8 Wang CC, Meyer JE. Radiotherapeutic management of the carcinoma of the nasopharynx. Analysis of 170 patients. Cancer 1971;28:566–70.[Web of Science][Medline]
9 Qin DX, Hu YH, Yan JH, Xu GZ, Cai WM, Wu XL, et al. Analysis of 1379 patients with nasopharyngeal carcinoma treated by radiation. Cancer 1988;61:1117–24.[Web of Science][Medline]
10 Al-Sarraf M, Pajak TF, Cooper JS, Mohiuddin M, Herskovic A, Ager PJ. Chemo-radiotherapy in patients with locally advanced nasopharyngeal carcinoma: a Radiation Therapy Oncology Group study. J Clin Oncol 1990;8:1342–51.[Abstract]
11 Huang SC, Lui LT, Lynn TC. Nasopharyngeal cancer study III. A review of 1206 patients treated with combined modalities. Int J Radiat Oncol Biol Phys 1985;11:1789–93.[Web of Science][Medline]
12 Souhami L, Rabinowits M. Combined treatment in carcinoma of the nasopharynx. Laryngoscope 1988;98:881–3.[Web of Science][Medline]
13
Bachouchi M, Cvitkovic E, Azli N, Gasmi J, Cortes-Funes H, Boussen H, et al. High complete response in advanced nasopharyngeal carcinoma with bleomycin, epirubicin and cisplatin before radiotherapy. J Natl Cancer Inst 1990;82:616–20.
14 Chatani M, Teshima T, Inoue T, Azuma I, Yoshimura H, Oshitani T, et al. Radiation therapy for nasopharyngeal carcinoma. Cancer 1986;57:2267–71.[Web of Science][Medline]
15
Dimery IW, Peters LJ, Goepfert H, Morrison WH, Byers RM, Guillory C, et al. Effectiveness of combined induction chemotherapy and radiotherapy in advanced nasopharyngeal carcinoma. J Clin Oncol 1993;11:1919–28.
16 Lin JC, Jan JS, Hsu CY. Neoadjuvant chemotherapy for advanced nasopharyngeal carcinoma. Am J Clin Oncol 1995;18:139–43.[Web of Science][Medline]
17 Teo PM, Leung TW, Chan AT, Yu P, Lee WY, Leung SF, et al. A retrospective study of the use of cisplatin–5-fluorouracil neoadjuvant chemotherapy in cervical-node-positive nasopharyngeal carcinoma (NPC). Eur J Cancer 1995;31B:373–9.
18 Rahima M, Rakowsky E, Barzilay J, Sidi J. Carcinoma of the nasopharynx. An analysis of 91 cases and a comparison of differing treatment approaches. Cancer 1986;58:843–9.[Web of Science][Medline]
19 Dimery IW, Legha SS, Peters LJ, Goepfert H, Oswald MJ. Adjuvant chemotherapy for advanced nasopharyngeal carcinoma. Cancer 1987;60: 943–9.[Web of Science][Medline]
20 Azli N, Armand JP, Rahal M, Wibault P, Boussen H, Eschwege F, et al. Alternating chemo-radiotherapy with cisplatin and 5-fluorouracil plus bleomycin by continuous infusion for locally advanced undifferentiated carcinoma nasopharyngeal type. Eur J Cancer 1992;28A:1792–7.
21 Al-Kourainy K, Crissman J, Ensley J, Kish J, Kelly J, Al-Sarraf M. Excellent response to cis-platinum based chemotherapy in patients with recurrent or previously untreated advanced nasopharyngeal carcinoma. Am J Clin Oncol 1988;11:553–7.[Web of Science][Medline]
22
Atichartakarn V, Kraiphibul P, Clongsusuek P, Pochanugool L, Kulapaditharom B, Ratanatharathorn V. Sequential chemotherapy and radiation for nasopharyngeal cancer: absence of long-term benefit despite a high rate of tumor response to chemotherapy. J Clin Oncol 1987;5:629–34.
23 Boussen H, Cvitkovic E, Wendling JL, Azli N, Bachouchi M, Mahjoubi R, et al. Chemotherapy of metastatic and/or recurrent undifferentiated nasopharyngeal carcinoma with cisplatin, bleomycin and fluorouracil. J Clin Oncol 1991;9:1675–81.[Abstract]
24
Al-Sarraf M, LeBlanc M, Giri PG, Fu KK, Cooper J, Vuong T, et al. Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: phase III randomized Intergroup Study 0099. J Clin Oncol 1998;16:1310–17.
25 Chan AT, Teo PM, Leung TW, Leung SF, Lee WY, Yeo W, et al. Prospective randomized trial conducted to compare chemo-radiotherapy against radiotherapy alone in the treatment of locoregionally advanced nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 1995;33:569–77.[Web of Science][Medline]
26 Chua DT, Sham JS, Choy D, Lorvidhaya V, Sumitsawan Y, Thongprasert S, et al. Preliminary report of the Asian–Oceanian Clinical Oncology Association randomized trial comparing cisplatin and epirubicin followed by radiotherapy versus radiotherapy alone in the treatment of patients with local-regionally advanced nasopharyngeal carcinoma. Cancer 1998; 83:2270–83.[Web of Science][Medline]
27
International Nasopharynx Study Group. Preliminary results of randomized trial comparing neoadjuvant chemotherapy (cisplatin, epirubicin, bleomycin) plus radiotherapy vs radiotherapy alone in stage IV (
N2, M0) undifferentiated nasopharyngeal carcinoma: a positive effect on progression-free survival. Int J Radiat Oncol Biol Phys 1996;35:463–9.[Web of Science][Medline]
28 International Union Against Cancer (UICC). In: Hermanek P, Sobin LH, editors. TNM Classification of Malignant Tumours, 4th ed. Heidelberg: Springer 1987.
29 WHO Handbook for Reporting Results of Cancer Treatment. Geneva: World Health Organization 1979;14–27.
30 Kaplan EL, Meier P. Nonparametric estimations from incomplete observations. J Am Stat Assoc 1958;53:475–81.
31 Peters LJ, Withers HR. Applying radiobiological principles to combined modality treatment of head and neck cancer – the time factor. Int J Radiat Oncol Biol Phys 1997;39:831–6.[Web of Science][Medline]
32 Tannock IF. Combined modality treatment with radiotherapy and chemotherapy. Radiother Oncol 1989;16:83–101.[Web of Science][Medline]
33 Byfield JE, Sharp TR, Frankel SS, Tang SG, Callipari FB. Phase I and II trial of five-day infused 5-fluorouracil and radiation in advanced cancer of the head and neck. J Clin Oncol 1984;2:406–13.[Abstract]
34 Merlano M, Vitale V, Rosso R, Benasso M, Corvo R, Cavallari M, et al. Treatment of advanced squamous-cell carcinoma of the head and neck with alternating chemotherapy and radiotherapy. N Engl J Med 1992;15:1115–21.
Received June 21, 2001; accepted September 17, 2001.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  W. J. Maloney and M. A. Weinberg A Comprehensive Analysis of Babe Ruth's Head and Neck Cancer J Am Dent Assoc, July 1, 2008; 139(7): 926 - 932. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Fuwa, T. Kodaira, H. Tachibana, T. Nakamura, and T. Daimon Dose Escalation Study of Nedaplatin with 5-Fluorouracil in Combination with Alternating Radiotherapy in Patients with Head and Neck Cancer Jpn. J. Clin. Oncol., March 1, 2007; 37(3): 161 - 167. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||