levoleucovorin and Nasopharyngeal-Neoplasms

Nasopharyngeal carcinoma (NPC) is a radiosensitive and chemosensitive tumour. The aim of this prospective study is to evaluate the toxicity and efficacy of an outpatient weekly neoadjuvant chemotherapy (NeoCT) plus radiotherapy for advanced NPC. From November 1998 to August 2001, 90 NPC patients meeting the following criteria were treated: (1) neck node >6 cm; (2) supraclavicular node metastasis; (3) skull base destruction/intracranial invasion plus multiple nodes metastasis; (4) multiple neck nodes metastasis with one of nodal size >4 cm; or (5) elevated serum LDH level. The NeoCT consists of cisplatin 60 mg m(-2), alternating with 5-fluorouracil 2500 mg m(-2) plus leucovorin 250 mg m(-2) (P-FL) by an outpatient weekly schedule for a total of 10 weeks. Local radiotherapy > or =70 Gy by conventional fractionation was delivered within 1 week after NeoCT. Patient compliance was rather good. Grade 3-4 toxicity of NeoCT included leucopaenia (7.8%), anaemia (18.9%), thrombocytopaenia (3.3%), nausea/vomiting (4.4%), and weight loss (1.1%). Response evaluated after NeoCT showed 73.3% complete response (CR) rate of primary tumour, 71.1% CR rate of neck nodes, and an overall CR rate of 57.8%. In all, 88 out of 90 patients received rebiopsy of primary tumour and 55 patients (62.5%) revealed pathological CR. After a median follow-up time of 24 months, one persistent disease and 18 relapses were noted. The 2-year nasopharynx disease-free, neck disease-free, distant disease-free, overall, and progression-free survival rates are 98.9, 95.9, 80.0, 92.1, and 77.5%, respectively. Preliminary data of the current study show that P-FL NeoCT plus radiotherapy is a low-toxic regimen with promising results on very advanced NPC patients and merits to be investigated in phase III trials.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Nasopharyngeal Neoplasms; Neoadjuvant Therapy; Neoplasm Invasiveness; Neoplasm Staging; Outpatients; Patient Compliance; Prospective Studies; Survival Rate; Treatment Failure

Topics: Bleomycin; Carcinoma, Squamous Cell; Drug Administration Schedule; Drug Therapy, Combination; Fluorouracil; Head and Neck Neoplasms; Humans; Hydroxyurea; Laryngeal Neoplasms; Leucovorin; Lip Neoplasms; Lymphatic Metastasis; Methotrexate; Mouth Neoplasms; Nasopharyngeal Neoplasms; Tongue Neoplasms

Nasopharyngeal carcinoma (NPC) is rare in children, accounting for <1% of all cases. Treatment most commonly includes radiotherapy but long-term side effects of such treatment can produce devastating cosmetic and functional sequelae in children. Chemotherapy may help to decrease the radiotherapy dose and limit the side effects of local therapies. However, little is known regarding the chemosensitivity of NPC tumors in pediatric patients.. Patients with American Joint Committee on Cancer (AJCC) Stage I/II disease (Stratum 01) received irradiation only. Patients with AJCC Stage III/IV disease (Stratum 02) received 4 courses of preradiation chemotherapy comprising methotrexate (120 mg/m2) on Day 1, with cisplatin (100 mg/m2) 24 hours later, 5-fluorouracil 1000 mg/m2 per day as a continuous infusion for 3 days, and leucovorin 25 mg/m2 every 6 hours for 6 doses. Irradiation was given after chemotherapy and consisted of 50.4 gray (Gy) to the upper neck and 45.0 Gy to the lower neck, with a boost to the primary tumor and positive lymph nodes for a total dose of 61.2 Gy.. One patient was enrolled in Stratum 01 and 16 evaluable patients were enrolled in Stratum 02. The median age of the patients was 13 years and 65% of the patients were black. All patients tested had evidence of Epstein-Barr virus infection. Two-thirds of the patients developed Grade 3-4 mucositis during chemotherapy. The overall response rate to induction chemotherapy was 93.7%. The overall 4-year event-free and overall survival rates (+/- the standard error) were 77%+/-12% and 75%+/-12%, respectively.. The current study demonstrated that childhood NPC was sensitive to chemotherapy and that chemotherapy before irradiation was feasible. Future trials should investigate equivalent efficacy with a reduced radiotherapy dose.

Topics: Adolescent; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Cisplatin; Combined Modality Therapy; Epstein-Barr Virus Infections; Fluorouracil; Herpesvirus 4, Human; Humans; Leucovorin; Methotrexate; Nasopharyngeal Neoplasms; Survival Rate

To evaluate the effect and acute toxicity of late course conformal radiotherapy combined with chemotherapy for stage III and IV a nasopharyngeal carcinoma (NPC).. Ninety-six patients with stage III and IV a NPC were randomly divided into 2 groups: test group (n = 46, undergoing late course conformal radiotherapy combined with chemotherapy) and control group (n = 50, undergoing conventional radiotherapy). Both groups were treated with one-period chemotherapy, including cisplantin, 5-fluouracil, and calcium folinate, before and after the radiotherapy. The radiotherapy of the test group consisted of 2 phases: 36.0 approximately 40.0 Gy in 18 approximately 20 fractions over 3.5-4 weeks as the first phase using conventional technique was delivered with 2 lateral opposing faciocervical fields, and then 30.0-46.0 Gy in 15-23 fractions over 3-4.5 weeks as the second phase using three-dimensional conformal radiotherapy (3D-CRT).. The rates of complete remission (CR), partial remission (PR), and no change (NC) of the test group were 95.65%, 4.35%, and 0, not significantly different from those in the control group (90.00%, 10.00%, and 0, P = 0.287). The 1-year survival rate of the test group was 100%, not significantly different from that of the control group (96.00%, P = 0.170). The nasopharyngeal 1 year control rate of the test group was 97.83%, significantly higher than that of the control group (78.00%, P = 0.03). The distant metastasis rate of the test group was 8.70%, not significantly different from that of the control group (12.00%, P = 0.596). The incidence rates of radiological caries and irradiation-induced otitis media in the test group was 4.25% and 17.39% respectively, both significantly lower than those in the control group (26.00% and 42.00% respectively, P = 0.004 and P = 0.000). There was no significant difference in the incidence of nausea, vomiting, leukopenia, and severity of acute mucositis between these 2 groups.. Late course conformal radiotherapy combined with chemotherapy effectively improves the disease control, delays the distant metastasis, and alleviates radioactivity damnification.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Drug Administration Schedule; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Nasopharyngeal Neoplasms; Radiotherapy, Conformal

To evaluate the toxicity and efficacy of concurrent chemoirradiation with cisplatin followed by adjuvant ifosfamide, 5-fluorouracil and leucovorin in patients with stage IVb nasopharyngeal carcinoma (NPC) PATIENTS AND METHODS: Between October 1998 and August 2001, 35 Chinese patients with stage IVb NPC (N3a:12, N3b:23) were treated with by concurrent chemoirradiation using cisplatin 100 mg/m2 on days 1, 22, and 43 of radiotherapy, followed by adjuvant chemotherapy with 1.4 g/m2, ifosfamide, 450 mg/m2 5-fluorouracil, and 20 mg/m2 leucovorin daily for 5 days and repeated every 3 weeks for three cycles. Radiotherapy was given using standard fractionation at 2 Gy/day to a total of 68 Gy to the nasopharynx and 66 Gy to the neck.. All patients completed the prescribed radiotherapy. Twenty-three patients (66%) completed all scheduled cycles of chemotherapy. The compliance rate for concurrent and adjuvant chemotherapy was 71% and 80%, respectively. Grade 3 mucositis occurred in 37%, and grade 3 dermatitis occurred in 11.5% during radiotherapy. Grade 3 neutropenia occurred in 17% during concurrent chemotherapy, and grade 3-4 neutropenia occurred in 48.5% during adjuvant chemotherapy. There were no treatment-related deaths. With a median follow-up of 31 months, the 3-year relapse-free rate was 60%, and the 3-year overall survival rate was 74%. Locoregional control was excellent, with a 3-year local and nodal relapse-free rate of 91% and 83%, respectively. Eleven patients (31%) had developed distant metastases, and the 3-year distant metastasis-free rate was 66%.. The chemotherapy regimen tested is practical with an acceptable compliance rate. Despite having a more advanced stage disease, the observed outcome of our patients seems to be comparable with other series using platinum-based adjuvant chemotherapy. Further investigation to confirm the benefit of using the study regimen in advanced stage NPC is warranted.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Chemotherapy, Adjuvant; Cisplatin; Combined Modality Therapy; Dermatitis; Female; Fluorouracil; Humans; Ifosfamide; Leucovorin; Leukopenia; Male; Middle Aged; Nasopharyngeal Neoplasms; Survival Rate; Vomiting

Since 1990, we have treated patients with advanced nasopharyngeal cancer with induction chemotherapy and concomitant chemoradiotherapy. We herein report the results of our experience.. From 1990 to 1999, 27 patients with locoregionally advanced nasopharyngeal cancer were treated with induction chemotherapy followed by concomitant chemoradiotherapy. Using the American Joint Committee on Cancer's 1992 stage classification, all patients were stage III (11%) or IV (89%). By histology, 63% were poorly differentiated carcinoma and 37% squamous cell carcinoma. The median age was 42 years. Three cycles of induction chemotherapy consisting of cisplatin, 5-fluorouracil, leucovorin and interferon-alpha2b were administered, followed by concomitant chemoradiotherapy consisting of seven cycles of 5-fluorouracil, hydroxyurea and once-daily radiotherapy (FHX) on a week-on week-off schedule. The median radiotherapy dose was 70 Gy.. Clinical response to induction chemotherapy was 100%, 54.2% complete response (CR) and 45.8% partial response. Clinical and/or pathological (37% of all patients had post-treatment biopsy with or without neck dissection) CR after FHX was 100%. At a median follow-up of 52 months, three failures were observed. Two patients have died of disease, one of local failure and one of distant metastases. One patient is alive with an isolated rib metastasis. At 5 years, actuarial locoregional control is 93% and actuarial distant control 92%. The overall survival at 3 and 5 years is 88% and 77%, respectively. Four patients died of unrelated illnesses and had no evidence of disease with respect to their nasopharyngeal cancer. The progression-free survival at 3 and 5 years is 92% and 86%, respectively. Thirty-three per cent of patients required a reduction in the chemotherapy dose due to acute toxicity. Chronic toxicity was not observed, with all patients able to eat orally without dietary restrictions.. Treatment of locoregionally advanced nasopharyngeal cancer with induction chemotherapy followed by concomitant chemoradiotherapy resulted in excellent overall survival with acceptable toxicity. These results are encouraging and warrant further investigation of intensified approaches.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Carcinoma, Squamous Cell; Cisplatin; Combined Modality Therapy; Disease-Free Survival; Female; Fluorouracil; Humans; Hydroxyurea; Interferon-alpha; Leucovorin; Male; Middle Aged; Nasopharyngeal Neoplasms; Neoadjuvant Therapy; Neoplasm Staging; Treatment Outcome

To evaluate the role of adjuvant chemotherapy in locally advanced nasopharyngeal carcinoma (NPC) patients, we conducted a randomized Phase III trial comparing radiotherapy (RT) followed by adjuvant chemotherapy to RT alone in patients with advanced NPC.. Between November 1994 and March 1999, 157 patients with Stage IV, M(0) (UICC/AJCC, 1992) advanced NPC disease were randomized to receive standard radiotherapy, as follows: 35-40 fractions, 1.8-2.0 Gy/fraction/day, 5 days/week, to a total dose 70-72 Gy with or without 9 weekly cycles of 24-h infusional chemotherapy (20 mg/m(2) cisplatin, 2,200 mg/m(2) 5-fluorouracil, and 120 mg/m(2) leucovorin) after RT. Of 157 patients enrolled, 154 (77 radiotherapy, 77 combined therapy) were evaluable for survival and toxicity analysis.. With a median follow-up of 49.5 months, the 5-year overall survival and relapse-free survival rates were 60.5% vs. 54.5% (p = 0.5) and 49.5% vs. 54.4% (p = 0.38) for the radiotherapy-alone group and the combined radiotherapy and adjuvant chemotherapy group, respectively. The Cox regression showed that the hazard rates ratio of combined treatment to RT alone was 0.673 (p value = 0.232); the 95% confidence interval was 0.352 and 1.288, respectively. Patients who received combined treatment had a lower systemic relapse rate than radiotherapy-alone patients, according to relapse pattern analysis. The incidence of leukopenia (>or= Grade 3) occurred in 17 out of 819 (2.1%) cycles of weekly chemotherapy. No patient developed moderate to severe mucositis (>or= Grade 3).. We conclude that adjuvant chemotherapy after RT for patients with advanced NPC has no benefit for overall survival or relapse-free survival.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cause of Death; Chemotherapy, Adjuvant; Cisplatin; Confidence Intervals; Disease-Free Survival; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Male; Middle Aged; Nasopharyngeal Neoplasms; Neoplasm Staging; Proportional Hazards Models; Radiotherapy Dosage; Survival Analysis

The incidence of nasopharyngeal carcinoma in Germany is relatively low in comparison with certain regions in south-east Asia. However, standardised therapeutical regimes are required in the treatment of these tumours.. Between August 1990 and December 1997, 25 patients with stage III and IV nasopharyngeal carcinoma received an accelerated and hyperfractionated radiotherapy with concurrent chemotherapy (5-FU and mitomycin C). The primary tumour and positive lymph nodes received a total dose of 72 Gy over a period of 6 weeks. In the first 3 weeks, irradiation fields were treated five times per week with 2 Gy per fraction. Thereafter, treatment was accelerated, giving two daily fractions of 1.4 Gy. Salvage surgery was offered for residual lymph node disease after radiotherapy.. The overall response rate defined as complete and partial response of the primary was 100%. Sixteen of the 25 patients were still alive and were free of any evidence of tumour recurrence or distant metastases at a mean follow-up period of 34 months (range 7-95 months). Six patients received salvage surgery. Only one of these six patients had histologically proven evidence of vital tumour. No severe late complications such as blindness or temporal lobe necrosis were observed.. The presented data are promising and show that the combination of hyperfractionated accelerated radiotherapy and chemotherapy is feasible and effective.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Chemotherapy, Adjuvant; Dose Fractionation, Radiation; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Mitomycin; Nasopharyngeal Neoplasms; Neoplasm Staging; Radiotherapy, Adjuvant; Salvage Therapy; Survival Analysis; Treatment Outcome

Survival in advanced nasopharyngeal carcinoma (NPC) is compromised by distant metastasis. Because mitomycin is active against hypoxic and G0 cells, which may help to eradicate micrometastasis, we investigated the effect of mitomycin-containing cisplatin-based induction chemotherapy.. Recruited for this study were American Joint Committee on Cancer (AJCC) 1992 staging system stage IV NPC patients with the following adverse features: obvious intracranial invasion, supraclavicular or bilateral neck lymph node metastasis, large neck node (> 6 cm), or elevated serum lactate dehydrogenase (LDH) level. Patients were given three cycles of chemotherapy before radiotherapy. The chemotherapy comprised a 3-week cycle of mitomycin, epirubicin, and cisplatin on day 1 and fluorouracil and leucovorin on day 8 (MEPFL).. From January 1994 to December 1997, 111 patients were recruited. The median follow-up period was 43 months. The actuarial 5-year overall survival rate was 70% (95% confidence interval [CI], 60% to 80%; n = 111). For patients having completed radiotherapy (n = 100), the 5-year locoregional control rate was 70% (95% CI, 55% to 84%) and the distant metastasis-free rate was 81% (95% CI, 73% to 89%). The 5-year distant metastasis-free rate of N3a and N3b disease of AJCC 1997 staging system were 79% (95% CI, 62% to 95%) and 74% (95% CI, 60% to 89%), respectively. By Cox multivariate analysis, high pretreatment serum LDH level (P = .04) and neck nodal enlargement before radiotherapy (P = .001) were adverse prognostic factors of survival.. The good 5-year survival of N3 disease supports the effectiveness of induction MEPFL in the primary treatment of advanced NPC. Further investigation to incorporate concurrent chemoradiotherapy is warranted.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Disease-Free Survival; Drug Administration Schedule; Epirubicin; Female; Fluorouracil; Humans; Leucovorin; Lymphatic Metastasis; Male; Middle Aged; Mitomycin; Nasopharyngeal Neoplasms; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Neoplasm Staging; Survival Analysis; Taiwan; Treatment Outcome

The aim of this study was to evaluate the efficacy and toxicity of ifosfamide, 5-fluorouracil (5-FU) and leucovorin (IFL) as a second-line chemotherapy regimen in patients with recurrent undifferentiated nasopharyngeal carcinoma (NPC) previously treated with platinum/5-FU. Between June 1997 and February 1999, 18 patients were entered into the study. 3 patients had loco-regional recurrence, 12 had distant metastases and 3 had both loco-regional recurrence and distant metastases. All patients had previously received platinum/5-FU as adjuvant or palliative treatments. The IFL regimen consisting of ifosfamide 1.2 g/m(2) (with mesna), 5-FU 375 mg/m(2) and leucovorin 20 mg/m(2) for 5 days and was repeated every 21 days. The dose of ifosfamide was escalated to 1.4 and 1.6 g/m(2) in subsequent cycles according to the bone marrow toxicity, and the dose of 5-FU to 450 and 525 mg/m(2) according to the severity of mucositis. Patients received a median of 3 cycles of IFL (range: 2-6), with a median total ifosfamide dose of 21 g/m(2) (range: 13-46) and a median total 5-FU dose of 6.75 g/m(2) (range: 4.1-14.7). The median follow-up was 10 months (range: 4-25). 9 patients (50%) achieved a partial response and 1 patient (6%) achieved a complete response, with an overall response rate of 56% (95% confidence interval (CI): 32-80%). For those patients who responded to IFL, 8 had subsequent disease progression on follow-up, with a median response duration of 7.1 months (95% CI: 5.3-8.9). The median time to progression for all patients was 6.5 months (95% CI: 4.2-8.7). 12 patients are still alive with an estimated 1-year survival probability rate of 51%. Treatments were well tolerated, only 1 patient had grade 3 emesis. None of the patients had grade 3/4 anaemia, leucopenia or thrombocytopenia, although IFL was discontinued in 1 patient because of persisting thrombocytopenia. IFL is an effective second-line regimen in patients with recurrent NPC and is well tolerated with mild toxicity. Combining platinum and IFL in chemonaïve patients may further improve the overall response rate and duration and is worth investigating in future trials.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Female; Fluorouracil; Follow-Up Studies; Humans; Ifosfamide; Leucovorin; Male; Middle Aged; Nasopharyngeal Neoplasms; Neoplasm Metastasis; Neoplasm Recurrence, Local; Platinum Compounds; Tomography, X-Ray Computed

The combination of cisplatin and 5-fluorouracil (5-FU) (PF) is the most popular regimen for treating metastatic nasopharyngeal carcinoma (NPC) but it is limited by severe stomatitis and chronic cisplatin-related toxicity. A novel approach including induction with mitomycin C, doxorubicin and cisplatin (MAP) and subsequent maintenance with weekly 5-FU and leucovorin (FL) were designed with an aim to reduce acute and chronic toxicity of PF. Thirty-two patients of NPC with measurable metastatic lesions in the liver or lung were entered into this phase II trial. Mitomycin C 8 mg m(-2), doxorubicin 40 mg m(-2) and cisplatin 60 mg m(-2) were given on day 1 every 3 weeks as initial induction. After either four courses or remission was achieved, patients received weekly dose of 5-FU 450 mg m(-2) and leucovorin 30 mg m(-2) for maintenance until disease progression. With 105 courses of MAP given, 5% were accompanied by grade 3 and 0% were accompanied by grade 4 stomatitis. The dose-limiting toxicity of MAP was myelosuppression. Forty per cent of courses had grade 3 and 13% of courses had grade 4 leukopenia. No grade 3 or 4 cisplatin-related toxicity was observed. The overall response rate was 94% (95% confidence interval (CI) 84.9-100%) with a complete response rate (CR) of 6% (95% CI: 0-15.2%) and a good partial response (PR) rate of 28% (95% CI 11.7-44.6%), which was optionally defined as observance of only equivocal lesion identifiable under imaging study. Twenty-seven cases entered weekly FL maintenance phase. The median duration of maintenance with weekly FL was 38 weeks (8-91 weeks). There was no grade 3 or 4 toxicity noted during weekly FL. The median progression-free survival and overall survival were 11.6+/-0.4 and 18.1+/-3.6 months respectively. Six patients with a median follow-up of 19.8 months (9.6-41.0 months) were still alive and five of them had disease under control with FL. Good responders (CR and good PR) had better survival than less satisfactory responders (PR and stable disease) (P = 0.05). From Cox's multivariate regression analysis, the only significant prognostic factor for survival was good response to MAP (P = 0.042). Liver metastasis was the only significant variable in the best subset regression model that predicted good response to MAP (CR and good PR) (P = 0.027). MAP was an effective combination for metastatic NPC with minimal stomatitis and cisplatin-related toxicity but had significant myelosuppression. Weekly FL was a maintenance

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Disease-Free Survival; Doxorubicin; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Mitomycin; Nasopharyngeal Neoplasms; Neoplasm Metastasis; Neoplasm Staging; Survival Rate; Time Factors

Topics: Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Cisplatin; Combined Modality Therapy; Drug Administration Schedule; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Nasopharyngeal Neoplasms; Prospective Studies; Radiotherapy Dosage

Cisplatin-based induction chemotherapy has been extensively tested in nasopharyngeal carcinoma for the improvement of local and systemic control and survival of this disease. In this study, we report the results of the treatment with induction chemotherapy in 40 patients with locally advanced carcinoma of the nasopharynx (LANPC) with four courses of cisplatin (P) 25 mg/m2 per day and 5-fluorouracil (F) 1000 mg/m2 per day both in a 4-days continuous infusion, with or without leucovorin (L) 250 mg/m2 per day in 2-hour infusion at the beginning of daily administration of PF, followed by sequential radiotherapy. All except one were in stage IV. The overall response after induction chemotherapy was 93%, with 55% CR and 38% PR. Definitive overall response after radiotherapy was 98%, with 80% CR and 18% PR. At a maximum follow up of 11 years, the overall survival rate is 55%. Induction chemotherapy with continuous infusion of PF with or without leucovorin followed by radiotherapy is a highly active regimen for the treatment of locally advanced nasopharyngeal carcinoma with response and survival rates comparable to other combinations of sequential or simultaneous chemotherapy and radiotherapy.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Carcinoma, Squamous Cell; Chemotherapy, Adjuvant; Cisplatin; Combined Modality Therapy; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Life Tables; Male; Middle Aged; Nasopharyngeal Neoplasms; Remission Induction; Survival Rate; Treatment Outcome

Cisplatin, 5-flourouracil (5-FU), and leucovorin (PFL) chemotherapy has been reported to be effective in the treatment of cancers but severe mucositis or neutropenia are dose limiting toxicities. This Phase II study evaluated the anticancer effect and the toxicities of a new weekly 24-hour infusional PFL chemotherapy in patients with nasopharyngeal carcinoma (NPC).. Forty-two patients with stage IV NPC were studied. Cisplatin 25 mg/m2/d, 5-FU 2200 mg/m2/d, and leucovorin 120 mg/m2/d were adminstered weekly by 24-hour intravenous continuous infusion in an outpatient setting. Clinical response and toxicity were evaluated weekly.. The complete response rate (CR) was 30% and the partial response (PR) rate 60% in the localized previously untreated group. The CR rate was 22.7% and PR rate 45.5% in local recurrent/metastatic group. The overall response rate was 79%. Eighty-one percent of patients who had no previous chemotherapy and 67% of patients who had previous chemotherapy responded to weekly PFL. There were no dose limiting toxicities. No patient had grade 3 or 4 mucositis or neutropenia. Thirty-two patients (76%) had no oral mucositis. Seven patients (17%) had grade 1 mucositis and 3 patients (7%) had grade 2 mucositis.. Elimination of dose limiting toxicities is possible using a weekly 24-hour infusion schedule of PFL chemotherapy while retaining significant anticancer activity as demonstrated in these patients with advanced NPC. To discover whether this schedule is superior to cisplatin and 5-FU or other PFL chemotherapy regimens requires further investigation.

Topics: Adult; Aged; Ambulatory Care; Antidotes; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Cisplatin; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Nasopharyngeal Neoplasms; Neoplasm Recurrence, Local; Neutropenia; Remission Induction; Stomatitis; Survival Rate

Systemic disease progression occurs in the majority of patients with locally advanced nasopharyngeal carcinoma (NPC). Although a variety of chemotherapeutic drugs have had tumoricidal activity, the roles of chemotherapy and optimal regimens must be further defined. Based on high response rates of Cisplatin, 5-Fluororacil and Leucovorin (PFL) in patients with advanced squamous cell cancers of the head and neck, we tested a new outpatient PFL chemotherapy program in patients with advanced NPC.. Patients with NPC and 1) previously untreated, locally advanced disease; 2) local regional recurrence (LR) after radiotherapy; or 3) metastatic disease were eligible for study. Cisplatin 20 mg/m2/d, 5-FU 800 mg/m2/d and Leucovorin 90 mg/m2/d were administered simultaneously by continuous 96-hour intravenous infusion every three weeks. Patients were evaluated for response, survival, and toxicity.. Thirty-five patients were studied. The response rates of PFL therapy were 100% (15% complete response [CR], 85% partial response [PR]) in 20 patients with locally advanced or locally recurrent disease, and 80% (13.3% CR, 67.7% PR) in 15 patients with metastatic disease. The overall median survival was 20 months after therapy (range, 2-21). The median survival rate for previously untreated, locally advanced patients was not reached. The median survival rate for previously treated, local recurrence was 34 months and for metastatic patients was 14 months. Mucositis and leukopenia were the dose-limiting toxicities (20-23%, grade III) and occurred more frequently in patients previously irradiated. No treatment-related deaths occurred.. Outpatient PFL chemotherapy is active, safe, and convenient for advanced stage nasopharyngeal carcinoma patients, and the overall toxicities are tolerable.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Drug Administration Schedule; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Nasopharyngeal Neoplasms

Authors carried out a review of 40 cases of recurrent and/or metastatic nasopharyngeal carcinoma (NPC) treated with cisplatin-based chemotherapy at the Division of Othorhinolaryngology and the Service of Chemotherapy of the University of Palermo between July 1984 and July 1992. All patients were treated with regimens comprising high dose cisplatin (80-100 mg m-2). Histologically there were 29 squamous cell and 11 undifferentiated NPC. Thirty-nine patients were evaluable for response and toxicity. The overall response rate was 64%, with a 20.5% complete response rate and a 43.5% partial response rate. The mean duration of complete responses was 10.2+months, while that of partial responses was 8.6+months. The mean survival of the whole group was 11.4+months, with four patients alive after 2 years of follow-up. No statistically significant difference in response rate and survival was found between patients with metastatic disease and those with locoregional recurrency, and between patients with squamous cell NPC and those with undifferentiated histology. The employed regimens have been generally well tolerated. These data confirm that NPC is a neoplasm highly responsive to chemotherapy. However, duration of objective response and survival are still largely unsatisfactory.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Carcinoma; Carcinoma, Squamous Cell; Cisplatin; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Male; Methotrexate; Middle Aged; Nasopharyngeal Neoplasms; Neoplasm Metastasis; Neoplasm Recurrence, Local; Retrospective Studies

A retrospective analysis was performed of 39 patients with locally advanced nasopharyngeal cancer treated with combined chemotherapy and radiation therapy during the last five years at our departments. There were 26 men and 13 women with median age 55 (24-75) years. Histology was squamous cell carcinoma in 6 patients and undifferentiated carcinoma in the remaining 33 patients. Induction chemotherapy consisted of either regimen A (cisplatin 100 mg/m2 day 1, 5-FU 1,000 mg/m2 days 2-6 as continuous infusion, bleomycin 15 mg days 15 and 29 i.m., mitomycin 4 mg/m2 day 22 and hydroxyurea 1,000 mg/m2 daily days 23-27) or regimen B (carboplatin 300 mg/m2 day 1, 5-FU 1,000 mg/m2 days 1-5 as continuous infusion and methotrexate 1.2 g/m2 day 14 with leucovorin rescue). After completion of induction chemotherapy 13 patients (33%) had complete remission (CR) and 19 (49%) partial remission (PR). The CR rate was increased after radiation therapy to 72%. Survival rates were 88% at 12 and 78% at 24 months. Median time to progression was 29.5 months. In conclusion, induction chemotherapy with a platinum-based regimen followed by radiation therapy achieved a high rate of local control. If the treatment also prolongs survival must, however, be studied by randomized trials.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Carboplatin; Carcinoma, Squamous Cell; Cisplatin; Combined Modality Therapy; Female; Fluorouracil; Humans; Leucovorin; Male; Methotrexate; Middle Aged; Nasopharyngeal Neoplasms; Retrospective Studies

Between April 1981 and December 1983, patients with locoregional carcinoma of the nasopharynx were treated with two courses of chemotherapy administered before radiation therapy. Chemotherapy consisted of methotrexate, bleomycin, and cisplatin, which were administered at 3-week intervals, and radiation therapy was scheduled to commence 3 weeks after the start of the second course. Forty-nine of 51 consecutive patients were treated; only one patient progressed on chemotherapy, and of 36 patients with measurable neck nodes, eight had complete and 19 had partial clearance (greater than 50% decrease in cross-sectional area) of these nodes when assessed before initiation of radiotherapy. Despite the high rate of tumor response (75%; 95% confidence limits, 59% to 91%), the actuarial survival and disease-free survival curves were almost identical to those recorded for a consecutive group of 140 historical controls of similar stage distribution treated with radiation alone. This chemotherapy provided a high rate of tumor remission, but did not appear to convey long-term benefit to patients when used before radiation therapy.

Topics: Actuarial Analysis; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Combined Modality Therapy; Female; Humans; Leucovorin; Male; Methotrexate; Middle Aged; Nasopharyngeal Neoplasms; Prognosis; Remission Induction

Nasopharyngeal carcinoma is an extremely rare pediatric malignancy predominantly occurring in adolescent males. Its multifactorial pathogenesis is most strongly associated with the exposure to Epstein-Barr virus in genetically susceptible hosts. In younger patients, more aggressive biological behavior has been observed, although the overall survival is better compared to adults. Due to its rarity and nonspecific clinical presentation, the diagnosis in children is often delayed and misinterpreted.. We report a case of a 16-year-old boy with stage IVB nasopharyngeal carcinoma. He presented with a painless palpable neck mass, nasal congestion and a history of occasional epistaxis and headaches. Four years after the completion of a multimodal treatment, the patient is in complete remission.. Although exceedingly rare, pediatricians should consider nasopharyngeal carcinoma in the differential diagnosis of palpable neck masses, especially in male adolescents. A multidisciplinary approach in the diagnosis, treatment, supportive care and follow-up is of utmost importance.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Cisplatin; Fluorouracil; Humans; Leucovorin; Lymph Nodes; Lymphatic Metastasis; Male; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms; Neck; Neoadjuvant Therapy; Neoplasm Staging; Radiotherapy; Tomography, X-Ray Computed

To investigate the effects of adjuvant chemotherapy in nasopharyngeal carcinoma (NPC) patients with persistently detectable plasma Epstein-Barr virus DNA (pEBV DNA) after curative radiation therapy plus induction/concurrent chemotherapy.. The study population consisted of 625 NPC patients with available pEBV DNA levels before and after treatment. Eighty-five patients with persistently detectable pEBV DNA after 1 week of completing radiation therapy were eligible for this retrospective study. Of the 85 patients, 33 were administered adjuvant chemotherapy consisting of oral tegafur-uracil (2 capsules twice daily) for 12 months with (n=4) or without (n=29) preceding intravenous chemotherapy of mitomycin-C, epirubicin, and cisplatin. The remaining 52 patients who did not receive adjuvant chemotherapy served as the control group.. Baseline patient characteristics at diagnosis (age, sex, pathologic type, performance status, T classification, N classification, and overall stage), as well as previous treatment modality, were comparable in both arms. After a median follow-up of 70 months for surviving patients, 45.5% (15 of 33 patients) with adjuvant chemotherapy and 71.2% (37 of 52 patients) without adjuvant chemotherapy experienced tumor relapses (P=.0323). There were a significant reduction in distant failure (P=.0034) but not in local or regional recurrence. The 5-year overall survival rate was 71.6% for patients with adjuvant chemotherapy and 28.7% for patients without adjuvant chemotherapy (hazard ratio 0.27; 95% confidence interval 0.17-0.55; P<.0001).. Our retrospective data showed that adjuvant chemotherapy can reduce distant failure and improve overall survival in NPC patients with persistently detectable pEBV DNA after curative radiation therapy plus induction/concurrent chemotherapy.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Chemotherapy, Adjuvant; Cisplatin; DNA, Viral; Drug Combinations; Epirubicin; Female; Fluorouracil; Herpesvirus 4, Human; Humans; Induction Chemotherapy; Leucovorin; Male; Middle Aged; Mitomycin; Nasopharyngeal Neoplasms; Neoplasm Recurrence, Local; Radiotherapy, Conformal; Retrospective Studies; Tegafur; Treatment Outcome; Uracil

The study aimed to evaluate the efficacy of concurrent chemoradiotherapy (CCRT) with platinum-based chemotherapy as a primary treatment for nasopharyngeal carcinoma (NPC) and to further compare the results of CCRT with these of neoadjuvant chemotherapy (NAC) followed by radiotherapy (RT).. Before 1998, 21 patients with NPC received NAC followed by RT (NAC-RT). Between 1999 and 2008, a total of 25 NPC patients received CCRT. The CCRT group received a regimen including docetaxel (50 mg/m(2), day1), cisplatin (CDDP, 60 mg/m(2), day4) and continuous 5-fluorouracil (5-FU) infusion (600 mg/m(2), day 1-5), the TPF regimen, or a regimen including CDDP (60 mg/m(2), day4), continuous 5-FU infusion (600 mg/m(2), day 1-5), methotrexate (MTX, 30 mg/m(2), day 1) and leucovorin (LV, 20 mg/m(2), day 1-5), PFML regimen. The CCRT group received 2 cycles of chemotherapy during definitive RT. The NAC group of patients received a PFML regimen.. The overall response rate after CCRT was 96%. The 3-year and 5-year disease-specific survival rates were 75.6% and 60.1%, respectively. In patients receiving NAC-RT, the 3-year and 5-year disease-specific survival rates were 84.1% and 67.3%, respectively. There was no difference observed in terms of survival rates between the group receiving CCRT and that receiving NAC-RT.. CCRT with the TPF or PFML regimen was tolerable, and the NPC patients receiving this treatment showed excellent survival rates. In comparison to the group receiving NAC-RT, CCRT had no advantage in terms of the survival rate. In the future, the control of distant metastasis might play an important role in improving the survival rate of patients with advanced NPC receiving CCRT.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Chemoradiotherapy; Chemotherapy, Adjuvant; Cisplatin; Docetaxel; Female; Fluorouracil; Humans; Induction Chemotherapy; Leucovorin; Male; Methotrexate; Middle Aged; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms; Neoadjuvant Therapy; Retrospective Studies; Taxoids

Nasopharyngeal carcinoma (NPC) is a disease that is highly responsive to various chemotherapeutic agents. In the metastatic setting, 2-drug combination chemotherapy generally provides a response rate of 55% to 75%, and median survival of 10 to 12 months. The objective of the current study was to assess the efficacy of a 3-drug combination followed by maintenance treatment in patients with metastatic NPC.. Patients with metastatic NPC were treated with a combination of gemcitabine at a dose of 1,000 mg/m(2), paclitaxel at a dose of 70 mg/m(2), and carboplatin at an area under the concentration-time-curve (AUC) of 2.5 on Days 1 and 8 every 21 days. Patients who achieved partial or complete response continued to receive weekly 5-fluorouracil at a dose of 450 mg/m(2) and leucovorin at a dose of 30 mg/m(2) for 48 weeks.. Twenty-eight patients were recruited. Twenty-two (79%) patients had >or=2 sites of disease. Toxicities were mainly from bone marrow suppression, with 79% grade 3/4 neutropenia, 32% grade 3/4 anemia, and 29% grade 3/4 thrombocytopenia (according to the National Cancer Institute Common Toxicity Criteria). The overall response rate to the 3-drug regimen was 86%, with a complete response rate of 11%. The median duration of response was 8 months and the median overall survival was 22 months.. This regimen of a 3-drug combination followed by maintenance is feasible and has demonstrated an encouraging response rate and overall survival.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Carboplatin; Deoxycytidine; Feasibility Studies; Female; Fluorouracil; Follow-Up Studies; Gemcitabine; Humans; Leucovorin; Liver Neoplasms; Lung Neoplasms; Lymphatic Metastasis; Male; Maximum Tolerated Dose; Middle Aged; Nasopharyngeal Neoplasms; Paclitaxel; Prognosis; Quality of Life; Survival Rate

Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Carcinoma; Case-Control Studies; Cisplatin; Combined Modality Therapy; Disease Progression; DNA, Viral; Fluorouracil; Genotype; Herpesvirus 4, Human; Humans; Infusions, Intravenous; Leucovorin; Nasopharyngeal Neoplasms; Neoplasm Metastasis; Neoplasm Recurrence, Local; Polymerase Chain Reaction; Sensitivity and Specificity; Survival Analysis

Topics: Carcinoma, Squamous Cell; Cisplatin; Clinical Trials as Topic; Combined Modality Therapy; Disease-Free Survival; Fluorouracil; Humans; Hydroxyurea; Interferon-alpha; Leucovorin; Nasopharyngeal Neoplasms; Sample Size; Time Factors

In nasopharyngeal carcinoma, both, a short metastasis-free interval after primary treatment and the occurrence of epidural metastasis have been associated with poor prognosis. We present the clinical course of a young patient with these two conditions and review the literature.. A 26-year-old male with stage T2N3M0 non-keratinizing carcinoma (WHO type 2) of the nasopharynx was treated with induction chemotherapy and radical radiotherapy, 6 months after documentation of a clinical complete remission, the patient experienced metastatic disease to the C7-D1 vertebral bodies associated with an epidural soft tissue mass. Since no further metastatic lesions were detectable, the patient was treated with radiotherapy alone (3 960 cGy/22 fractions).. Treatment resulted in compete resolution of neurological and radiological signs of the disease and the patient continues to be disease-free, 32 months after salvage treatment. In a literature search, we identified 54 reported cases with long-term survival after treatment for metastatic nasopharyngeal cancer. The vast majority of them had primary tumors with undifferentiated histology and was treated with combination chemotherapy. In 25 of them, radiotherapy was given as consolidation therapy (in 19 cases for bone and in six cases for mediastinal lymph node metastases).. Epidural metastatic disease from a nasopharyngeal carcinoma is highly sensitive to moderate doses of fractionated radiotherapy. MR imaging is essential for the detection of relevant soft tissue disease extensions within the epidural space and proper selection of the radiation target volume in vertebral metastases. In patients with nasopharyngeal carcinoma, the occurrence of a solitary epidural metastasis after a short metastasis-free interval is not incompatible with long-term survival.

Topics: Adult; Antimetabolites, Antineoplastic; Antineoplastic Agents; Carcinoma; Cervical Vertebrae; Cisplatin; Combined Modality Therapy; Dose Fractionation, Radiation; Epidural Neoplasms; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Magnetic Resonance Imaging; Male; Nasopharyngeal Neoplasms; Prognosis; Radiotherapy Dosage; Radiotherapy Planning, Computer-Assisted; Thoracic Vertebrae; Time Factors

Distant metastasis rather than locoregional recurrence is the major site of failure after adequate radiotherapy in nasopharyngeal carcinoma (NPC). The aim of this study is to evaluate the toxicity and survival of outpatient weekly 24-hour infusion adjuvant chemotherapy for NPC patients with high-risk of distant failure.. Our definition of high-risk NPC included patients with (1) 1992 AJCC staging system of N3, T4N2, or N2 with one of nodal size > 4 cm; (2) supraclavicular node metastasis; and (3) residual disease after radiotherapy or neck relapse. From August 1994 to August 1997, 41 NPC patients matching the preceding criteria agreed to receive weekly PFL (cisplatin 25 mg/m(2), 5-fluorouracil 1250 mg/m(2), and leucovorin 120 mg/m(2)) adjuvant chemotherapy for a total of 18 weeks. Clinical data of another 88 patients with similar disease status who did not receive adjuvant chemotherapy during the same period were collected and analyzed for comparison. Survival analysis was investigated by the Kaplan-Meier method and the Cox proportional hazards model.. A total of 700 weekly chemotherapy doses was delivered to 41 patients. The ratio of actual/planned dose delivery was 94.9%. Grade 3-4 toxicity of adjuvant chemotherapy included leucopenia (7.3%), anemia (2.4%), thrombocytopenia (2.4%), and nausea/vomiting (2.4%). After a median follow-up of 70 months, 26.8% (11 of 41) and 47.7% (42 of 88) of patients in PFL and no adjuvant chemotherapy groups had distant metastasis (p =.0247). The 5-year metastasis-free survival rates were 71.9% for the PFL group compared with 48.4% for no adjuvant chemotherapy patients (p =.0187). The 5-year overall survival rates were 53.7% (PFL group) and 38.3% (no adjuvant chemotherapy group), respectively (p =.0666). Multivariate Cox analysis showed PFL adjuvant chemotherapy was the independent factor that predicted metastasis-free survival after adjustment for other variables.. Outpatient weekly 24-hour continuous infusion PFL adjuvant chemotherapy is a well-tolerated regimen with promising results in high-risk NPC patients and merits investigation in phase III studies.

Topics: Adolescent; Adult; Aged; Ambulatory Care; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Chemotherapy, Adjuvant; Cisplatin; Disease-Free Survival; Drug Administration Schedule; Female; Fluorouracil; Humans; Leucovorin; Lymphatic Metastasis; Male; Middle Aged; Nasopharyngeal Neoplasms; Neoplasm Recurrence, Local; Neoplasm, Residual; Patient Compliance; Proportional Hazards Models; Risk Factors; Survival Analysis; Taiwan

Nasopharyngeal carcinoma (NPC) is one of the dominant cancers in South China and Taiwan. Although NPC is highly chemosensitive, the use of chemotherapy for treating patients with recurrent or metastatic NPC has not been very successful. The emergence of drug resistance may be one of the major reasons. However, the mechanisms of drug resistance of NPC have never been addressed before. In this study, we sought to clarify the role of classical drug resistance markers in predicting the chemosensitivity and the prognosis of patients with advanced NPC.. In a cohort of 202 consecutive patients diagnosed at the Department of Pathology of the National Taiwan University Hospital, 44 patients with adequately preserved pretreatment tumor tissues and complete clinical information regarding the details of chemotherapy and tumor response were identified. The expression of multidrug resistance (MDR1), glutathione-S-transferase-pi (GSTpi), and p53 were determined by immunohistochemistry. Tumor response to chemotherapy and survival of the patients were the endpoints of this analysis.. Thirty-four patients received cisplatin-based regimens, and 28 of them were enrolled in a prospective trial using a doxorubicin-containing regimen. The overall response rate was 70%. Expression of MDR1 was seen in only 5 cases (11%) and was associated with a significantly worse overall survival, yet did not appear to predict chemoresistance to the doxorubicin-containing regimen. Overexpression of p53 was seen in 22 patients, and surprisingly, was correlated with chemoresponse and a trend towards better survival. GSTpi expression was demonstrated in 13 cases (30%) and was not correlated with chemoresistance to cisplatin-containing regimens and overall survival.. In this relatively small cohort, positive MDR1 immunostaining predicted a poor overall survival for recurrent or metastatic NPC patients receiving chemotherapy. Overexpression of p53 by immunohistochemical staining, however, was associated with a better response rate to systemic chemotherapy and a trend towards better survival.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; ATP Binding Cassette Transporter, Subfamily B, Member 1; Biomarkers, Tumor; Carcinoma, Squamous Cell; Cisplatin; Doxorubicin; Female; Fluorouracil; Glutathione S-Transferase pi; Glutathione Transferase; Humans; Immunoenzyme Techniques; Isoenzymes; Leucovorin; Male; Middle Aged; Mitomycin; Nasopharyngeal Neoplasms; Neoplasm Recurrence, Local; Prognosis; Prospective Studies; Survival Rate; Tumor Suppressor Protein p53

Nasopharyngeal carcinoma is a common cancer in South East Asia. In the early stages, radiotherapy alone may achieve sustained control, but once metastasis occurs, it becomes an incurable disease with limited survival time. We report a case of nasopharyngeal carcinoma, initial stage T4N0M0, diagnosed in 1985 in a patient aged 36 years who received 70 Gy radiotherapy to the head and neck region. In 1988, relapse occurred with multiple lung metastases. The patient received many chemotherapy regimens with a very good response, including near complete remission with the first treatment regimen of cisplatin, 5-fluorouracil and leucovorin for lung metastases, and with the fifth chemotherapy regimen of ifosfamide as a single agent. After ifosfamide treatment, there was residual fibrotic change in the lung and complete disappearance, lasting for almost a year, of the liver and bone lesions. The patient eventually died in July 1995 due to progressive disease. Prolonged survival after mainly thoracic metastasis is possible in patients with nasopharyngeal carcinoma, especially if the tumor is chemo-responsive.

Topics: Adult; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Cisplatin; Combined Modality Therapy; Drug Administration Schedule; Fluorouracil; Humans; Ifosfamide; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male; Nasopharyngeal Neoplasms; Survivors

Topics: Antidotes; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Drug Administration Schedule; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Nasopharyngeal Neoplasms

The role of a membrane-associated folate binding protein (mFBP) in transport of folate analogues was investigated in three epithelial cell lines that were grown in high folate medium and folate-conditioned medium and express different levels of mFBP: human nasopharyngeal KB cells, monkey kidney MA104 cells, and IGROV-I ovarian carcinoma cells. Folate analogues were selected for which mFBP exhibits a low affinity, i.e., methotrexate (MTX) and 10-ethyl-10-deazaaminopterin (10-EdAM) or a (moderately) high affinity as compared to folic acid, i.e., N-(5[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl(-N-m ethylamino]-2-theonyl)-L-glutamic acid (ZD1694), N10-propargyl-5,8-dideazafolic acid (CB3717), and 5,10-dideazatetrahydrofolic acid. Regardless of the medium folate status, growth inhibition studies with IGROV-I and MA104 cells demonstrated a lack of correlation between the affinity of mFBP for the antifolate drugs and their sensitivity profile; both cell lines were highly sensitive to growth inhibition by MTX, 10-EdAM, ZD1694 and 5,10-dideazatetrahydrofolic acid, but were insensitive for CB3717. The same drug sensitivity profile was observed for KB cells, with the exception that these cells were also sensitive to growth inhibition by CB3717 but only in folate-conditioned medium. This overall drug sensitivity profile appeared to correlate with the differential efficiency of drug transport via the "classical" reduced folate/MTX carrier (RFC), rather than by mFBP. Characteristics that further supported functional RFC activity in KB, IGROV-I, and MA104 cells included: (a) the growth inhibitory effects of the drugs could be prevented by the reduced folate leucovorin rather than by folic acid; (b) rates for uptake of [3H]10-EdAM were 2-4-fold higher than for [3H]MTX at 1 microM extracellular concentrations and coincided with the affinity of the RFC for these drugs, rather than those of the mFBP; (c) uptake of [3H]10-EdAM and [3H]leucovorin was markedly inhibited by leucovorin and 10-EdAM, respectively, or by an N-hydroxysuccinimide ester of MTX (irreversibly labeling RFC) but only to a minor extent by folic acid or an N-hydroxysuccinimide ester of folic acid (irreversibly labeling mFBP); and, finally, (d) labeling with an N-hydroxysuccinimide ester of [3H]MTX identified a protein with a molecular weight within the range of that reported for the RFC in human leukemic cells. Altogether, these results indicate that both RFC and mFBP are coexpressed in three epithe

Topics: Aminopterin; Animals; Carrier Proteins; Cell Division; Female; Folate Receptors, GPI-Anchored; Folic Acid; Folic Acid Antagonists; Glutamates; Haplorhini; Humans; Kidney; Leucovorin; Methotrexate; Nasopharyngeal Neoplasms; Ovarian Neoplasms; Quinazolines; Receptors, Cell Surface; Tetrahydrofolates; Thiophenes; Tumor Cells, Cultured

The effects of extracellular folate concentration on intracellular folate and phosphoribosylpyrophosphate (PRPP) levels and the cytotoxicity of methotrexate and 5-fluorouracil were studied in human KB cells grown in fetal bovine serum-supplemented Eagle's minimum essential medium, which contained standard high folic acid levels (2.3 microM) (standard or S medium), or folic acid-free serum-supplemented medium containing approximately 4 nM 5-methyltetrahydrofolate (physiological or P medium), a folate level and form more comparable to that in normal human serum. Macrocytosis and prolongation of the doubling time by 150% were observed after 5-10 serial passes in P medium, but after 10-15 serial passes, KB cells became "adapted" to P medium with return of size and doubling time to values indistinguishable from cells maintained in S medium. Cellular folate levels fell, and marked elevations in PRPP levels from 68 +/- 43 to 642 +/- 287 pmol/mg cell protein (mean +/- SD) were observed as KB cells were serially passed through P medium. Human leukemia HL-60 and K562 cells and MJY-alpha mouse mammary tumor cells serially passed in P medium also exhibited 10- to 20-fold elevations in PRPP levels. Glucose consumption, glucose decarboxylation, thymidine and adenosine specific uptake, thymidine incorporation into DNA, and 5-fluorouracil uptake were studied in KB cells with elevated and control PRPP levels. As determined by clonal assay, despite elevated PRPP levels, KB cells cultured in P medium were less sensitive to 5-fluorouracil than cells cultured in S medium unless exogenous folate was added. These data support the concept that endogenous folate levels may be inadequate for optimal 5-FU pharmacological action in KB cells with a modulated increase in PRPP levels.

Topics: Adenosine; Carcinoma, Squamous Cell; Cell Survival; Fluorouracil; Folic Acid; Glucose; Humans; KB Cells; Leucovorin; Leukemia, Myeloid, Acute; Methotrexate; Nasopharyngeal Neoplasms; Pentosephosphates; Phosphoribosyl Pyrophosphate; Thymidine

Topics: Antineoplastic Agents; Carcinoma; Chemotherapy, Cancer, Regional Perfusion; Fluorouracil; Head; Head and Neck Neoplasms; Humans; Leucovorin; Melanoma; Melphalan; Methotrexate; Mouth Neoplasms; Nasopharyngeal Neoplasms; Paranasal Sinus Neoplasms; Sarcoma; Thiotepa; Vinblastine

Topics: Adult; Chemotherapy, Cancer, Regional Perfusion; Female; Humans; Leucovorin; Male; Methotrexate; Middle Aged; Nasopharyngeal Neoplasms

Topics: Carcinoma; Carcinoma, Squamous Cell; Carcinoma, Transitional Cell; Geriatrics; Head and Neck Neoplasms; Humans; Infusions, Parenteral; Laryngeal Neoplasms; Leucovorin; Maxillary Neoplasms; Methotrexate; Nasopharyngeal Neoplasms; Neoplasm Metastasis; Neoplasms; Orbital Neoplasms; Palatal Neoplasms; Temporal Arteries; Tongue Neoplasms; Toxicology