Retrospective case series of gemcitabine plus cisplatin in the treatment of recurrent and metastatic nasopharyngeal carcinoma

To evaluate the efficacy and toxicity of gemcitabine plus cisplatin (GC) chemotherapy in patients with recurrent and metastatic nasopharyngeal carcinoma (NPC), 75 patients of Chinese ethnicity with recurrent and metastatic NPC received a combination of gemcitabine 1000 mg/m² on days 1 and 8, and cisplatin 25 mg/m² on days 1, 2 and 3 of a 21-day cycle. All patients were ineligible for re-irradiation or surgery. Of the 75 patients, 4 achieved a complete response, and 28 patients achieved a partial response, for an overall response rate of 42.7%. The 1-year survival rate was 33.9%, and median progression-free survival and overall survival were 5.6 and 9.0 months, respectively. Grade 3 and 4 toxicities were uncommon. Conclusion: this GC regimen was effective and well tolerated by patients with recurrent and metastatic NPC. The results were comparable with most reports in the recent literature.     

Biweekly low-dose sequential gemcitabine, 5-fluorouracil, leucovorin, and cisplatin (GFP): a highly active novel therapy for metastatic adenocarcinoma of the exocrine pancreas

Phase II studies have suggested an improved response rate and acceptable toxicity profile associated with gemcitabine combinations compared to gemcitabine alone for treatment of metastatic adenocarcinoma of the pancreas. The GFP regimen (gemcitabine, 5-fluorouracil, leucovorin, and cisplatin) is based on laboratory evidence of disease-specific chemotherapy interaction.[8] This retrospective analysis examined the outcome of 49 consecutive patients with histologically confirmed metastatic pancreatic adenocarcinoma treated between July 1998 and September 2000. Day 1 treatment consisted of gemcitabine 500 mg/m² over 30 minutes and then leucovorin 300 mg bolus, 5-fluorouracil (5-FU) 400 mg/m² bolus, followed by infusional 5-FU 600 mg/m² over 8 hours. Day 2 consisted of leucovorin 300 mg bolus, 5-FU 400 mg/m² bolus, followed by cisplatin 50-75 mg/m² over 30 minutes and then infusional 5-FU 600 mg/m² over 8 hours. Treatment was administered every 2 weeks. Median patient age was 61.5 years, 74% were men, and 20 patients had refractory disease (11 patients had disease progression upon gemcitabine-based therapy). Grade 3-4 toxic effects (% patients) consisted of neutropenia (30%), thrombocytopenia (14%), anemia (8%), and neutropenic fever (2%). Grade 3-4 nonhematological toxicities (% patients) consisted of neuropathy (14%), ototoxicity (8%), nephrotoxicity (6%), nausea/vomiting (14%), and mucositis (10%). The majority of dose reductions were made for neuropathy or cytopenias. Filgrastim and erythropoietin were given as needed to promote dose intensity. Eight patients attained a partial response (PR) by RECIST criteria. Fourteen had stable disease (SD). Two patients attaining PR and two attaining SD had progressive disease with prior gemcitabine-based therapy. The median time to disease progression (TTP) from GFP start was 9 weeks. For all 49 patients, the median overall survival (OS) from GFP start was 10.6 months, 12-month survival was 46%, and 24-month survival was 30%. Notably, upon disease progression, 31 patients continued to receive the GFP regimen with irinotecan 80 mg/m² inserted on day 1 following gemcitabine, the G-FLIP regimen (gemcitabine, 5-fluorouracil, leucovorin, irinotecan, and cisplatin). Measured from G-FLIP initiation, the TTP for the 31 patients treated sequentially was 10 weeks, and for the 14 patients attaining SD or PR the TTP was 25 weeks. The median overall survival measured from GFP initiation was 11.8 months. The response rate, non-cross resistance, TTP, OS, and tolerability warrant prospective development of this novel combination. This experience also demonstrates that adding a single new drug such as irinotecan to the same first-line chemotherapy combination upon disease progression may be an important alternative for the treatment of relapsed/resistant cancer.     

Phase I study of twice-weekly gemcitabine and concurrent thoracic radiation for patients with locally advanced non–small-cell lung cancer

Purpose: To determine the maximum tolerated dose (MTD) and dose-limiting toxicity of twice-weekly gemcitabine and concurrent thoracic radiation in patients with Stage IIIa/IIIb non–small-cell lung cancer (NSCLC).

Methods and Materials: Seventeen patients with histologically confirmed Stage IIIa and IIIb NSCLC were studied. Gemcitabine was administered via a 30-min i.v. infusion twice weekly for 6 weeks concurrent with 60 Gy of thoracic radiation. Gemcitabine, starting at a twice-weekly dose of 10 mg/m² (20 mg/m²/week), was escalated in 10–15 mg/m² increments in successive cohorts of 3 to 6 patients until dose-limiting toxicity was observed.

Results: Of the 17 patients entered, 16 were evaluable for toxicity. The dose-limiting toxicity at 50 mg/m² given twice weekly (100 mg/m²/week) was Grade 3 pneumonitis observed in 1 patient, Grade 3 pulmonary fibrosis in a second patient, and Grade 4 esophagitis observed in two additional patients. Twice-weekly gemcitabine at a dose of 35 mg/m² was determined to be the MTD. The overall response rate for the 16 evaluable patients was 88%. The median survival for the entire group is 16.0 months.

Conclusions: The MTD of twice-weekly gemcitabine is 35 mg/m² (70 mg/m²/week) given with thoracic radiation. A Phase II study within the Cancer and Leukemia Group B to ascertain the potential efficacy of this treatment regimen is in development.     

Phase II study of gemcitabine plus paclitaxel in metastatic breast cancer patients with prior anthracycline exposure

Chemotherapy provides palliation and modest prolongation of symptom-free survival in metastatic breast cancer. Taxane containing regimens are commonly considered to be among the initials in metastatic setting due to earlier use of anthracyclines in the course of breast cancer. Therefore, we conducted this Phase II study to assess efficacy and safety of gemcitabine plus paclitaxel (GT) combination therapy in anthracycline pretreated metastatic first-line setting. Patients and Methods: The study enrolled 26 women with pathologically confirmed and measurable metastatic breast cancer who were previously treated with anthracycline but no prior chemotherapy for metastatic disease. Twenty six and twenty four patients were eligible for toxicity and efficacy evaluations respectively. Mean age was 47.3 years and median ECOG performance status was 0. Twenty patients (76.9 percent) had visceral metastases, most commonly located in liver and lung. Treatment schedule was as follows: paclitaxel 175 mg/m² was administered intravenously in 3 hours on Day 1 and gemcitabine 1000 mg/m² was administered intravenously in 30 minutes on Day 1 after paclitaxel application, and on Day 8 every 21 days. Results: Objective response rate was 41.7 percent (95 percent CI: 21.9-61.4) with 16.7 percent (95 percent CI: 1.7-31.6 percent) CR, and 25.0 percent (95 percent CI: 7.6-42.3 percent) PR. Median time to progression and overall survival were 9.6 and 14.5 months, respectively. Grade 3-4 toxicity was observed in 34.6 percent (9) patients. Treatment of two patients was discontinued due to toxicity, consisting of Grade 3 hypersensitivity reactions and Grade 4 infections in one patient each. Dose reductions due to myelotoxicity were performed in 4 (15.3 percent) patients. Hematologic toxicities were generally manageable with appropriate dose modifications and supportive care. Conclusion: Gemcitabine and paclitaxel combination regimen is effective and has manageable toxicity profile as first line metastatic setting.     

Phase I trial of fixed dose rate infusion gemcitabine with gefitinib in patients with pancreatic carcinoma

Purpose: To determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of gemcitabine using a fixed dose rate infusion (FDRI) in combination with gefitinib in patients (pts) with pancreatic adenocarcinoma (PCa). Patients and methods: Patients with advanced PCa were given gemcitabine at the FDRI of 10 mg/m²/min IV on Days 1, 8, and 15 of a 28-day cycle. Dose levels of 1000, 1200, and 1500 mg/m² were evaluated. Oral gefitinib 250 mg was given daily. DLTs were defined as 2 instances of Grade 3 hematologic or 4 nonhematologic or any Grade 4 hematologic toxicity. At least 4 patients were treated at each dose level. Dose escalation occurred in the absence of DLTs. Results: Five women and 8 men were enrolled. Median age was 59 and performance status 1. All had metastatic disease. Four patients received prior adjuvant chemoradiation for PCa, and one chemotherapy for lung cancer. Median cycles were 4 per patient. The MTD was 1,200 mg/m². Toxicity was predominantly hematologic. At 1,500 mg/m², 1 patient had Grade 4 granulocytopenia and 3 patients Grade 3 granulocytopenia. Overall, 8 patients (60 percent) developed Grade 1 or 2 acneiform rashes. One patient had Grade 3 vomiting; no significant diarrhea or liver toxicity was seen. There were no objective responses seen. Median time to progression and overall survival were 4.57 months and 7.13 months, respectively. Conclusion: Combining FDRI gemcitabine with gefitinib is feasible and tolerable. The recommended dose of gemcitabine is 1,200 mg/m² when used with gefitinib 250 mg daily.     

Gemcitabine combined with docetaxel for the treatment of unresectable pancreatic carcinoma

Purpose. To assess the efficacy and toxicity of combination therapy with gemcitabine and docetaxel in patients with unresectable pancreatic carcinoma. Patients and Methods. Thirty-four patients with unresectable stage III, IVA, and IVB pancreatic carcinoma were eligible for this study. The first 18 patients received gemcitabine 800 mg/m² intravenously (IV) on days 1, 8, and 15 and docetaxel 75 mg/m² IV on day 1, repeated every 28 days. Due to a high incidence of myelosuppression in this first group, the treatment schedule was modified in the remaining patients to gemcitabine 1,000 mg/m² IV and docetaxel 40 mg/m² IV on days 1 and 8 of a 21-day schedule. The primary study endpoints were objective response rate and duration of survival. Results. Ten of 33 evaluable patients achieved a partial response, for an overall response rate of 30.3% (95% CI, 16.21%-48.87%). Partial responses noted in the pancreas and a variety of metastatic sites were maintained for 4 to 12 months (median 6 months). Twelve additional patients (36%) experienced stable disease. The median time to progression was 6 months, and median survival was 10.5 months. The toxicity profile of the modified gemcitabine/docetaxel schedule was more favorable than that associated with the initial regimen, particularly with respect to hematologic toxicity. Conclusion. The response and survival data reported here for combination therapy with gemcitabine and docetaxel are encouraging given the poor prognosis associated with unresectable pancreatic cancer. These data suggest that gemcitabine plus docetaxel may be more effective than either agent alone in the treatment of pancreatic cancer and warrants further study.     

Phase II study with gemcitabine, ifosfamide and cisplatin in advanced non-small cell lung cancer

The aim of the present study was to determine the clinical activity and toxicity of a novel chemotherapy combination regimen of gemcitabine, ifosfamide and cisplatin (GIP), administered every 3 weeks, in patients with inoperable non-small cell lung cancer (NSCLC). From October 1998 to July 1999, 18 previously untreated stages IIIb (4) and IV (14) patients were enrolled into the study. Gemcitabine and ifosfamide (with mesna as uroprotection) was administered on days 1 and 6, at a dose of 1000 and 1500 mg/m², respectively; and cisplatin was given on day 1 at a dose of 60 mg/m², every 3 weeks. All 18 patients were evaluable for response and toxicity profiles. One patient achieved a complete response, and 11 patients achieved a partial response, with an overall response rate of 66.7% (95% CI, 45–89%). The main toxicity was hematological, a NCI grade 3–4 neutropenia in 16 patients (88.9%) during the treatment course. Febrile neutropenia occurred in three patients (16.6%). Grade 3 anemia occurred in eight patients (44.4%) and grade 3–4 thrombocytopenia occurred in 11 patients (61.1%). Non-hematological toxicity was mild and tolerable. No toxic death occurred. The median survival was 12.7 months and 1 year survival was 58.4%. The GIP combination chemotherapy produced a high response rate in advanced NSCLC; however, there was a relatively high percentage of hematological toxicity that still could be tolerated. A randomized trial comparing GIP to a two-drug combination of gemcitabine and cisplatin is planned.     

A phase I human trial of mitoguazone and gemcitabine sequential bi-weekly treatment of cancer patients

Our previous studies have demonstrated the existence of synergism in a combination therapy using mitoguazone and gemcitabine when the mitoguazone is administered 24 hours before gemcitabine. Based on the cell culture and animal experimental results, a phase I clinical trial was performed in order to determine the toxicity of the combined treatment. Mitoguazone and gemcitabine were administered sequentially: mitoguazone on day 1 and gemcitabine on day 2. This cycle was repeated every 2 weeks. The dosages of these two drugs were varied between patients. Ten patients were enrolled in the study. Six patients began treatment at dose level 1 (mitoguazone 500 mg/m², gemcitabine 1500 mg/m²), three at dose level 2 (mitoguazone 500 mg/m², gemcitabine 2000 mg/m²), and one at dose level 3 (mitoguazone 600 mg/m², gemcitabine 2000 mg/m²). Dose-limiting toxicity (DLT) was only observed in two patients treated at dose level 1 and one patient treated at dose level 3, while all the other patients only experienced nonhematologic toxicity, such as asthenia and mucositis. Two melanoma patients showed responses (one partial and one minor) to the treatment. One lymphoma patient also showed a brief partial response. This phase I trial indicated that the combination of mitoguazone and gemcitabine had limited but noticeable activity for treatment of cancer patients. Further study on the toxicity and on the effect of the scheduled mitoguazone-gemcitabine combination is needed.     

Phase I trial of gemcitabine and paclitaxel in advanced solid tumors

Purpose. Gemcitabine and paclitaxel are chemotherapeutic agents with clinical antitumor activity in a broad range of malignant solid tumors. Because of preclinical synergy, unique mechanisms of action and resistance, and nonoverlapping toxicities, gemcitabine and paclitaxel combinations are attractive for testing in clinical trials. Prior weekly gemcitabine and paclitaxel regimens administered on a 28-day cycle have been limited by cumulative hematological toxicity on day 15, thus reducing the planned gemcitabine dose intensity. We therefore conducted a phase I trial of a 21-day schedule of weekly gemcitabine and paclitaxel to determine the tolerability, maximum tolerated dose (MTD), and preliminary estimates of efficacy of this regimen. Patients and Methods. Forty-one patients with advanced malignant solid tumors were accrued. Gemcitabine was given at a fixed dose of 1000 mg/m² while paclitaxel was administered at an initial dose of 60 mg/m², then escalated by 15 mg/m² increments over seven dose levels to a prospectively planned maximum dose of 150 mg/m². Both agents were infused intravenously on days one and eight every 21 days. At least three patients were enrolled per dose level. No intrapatient dose escalation was allowed. Results. All patients were assessable for toxicity and 31 were assessable for response. The regimen was generally well-tolerated. Dose-limiting thrombocytopenia was observed in one patient at a paclitaxel dose of 135 mg/m²/week (dose level 6). After expansion of this dose level by 14 additional patients, no further dose-limiting toxicities were observed although one patient at dose level seven died of neutropenic sepsis after completing three cycles. There were eight partial responders for an overall response proportion of 26% (95% CI: 11, 41). Twelve patients (39%) had stable disease. Conclusion. This 21-day schedule of gemcitabine and paclitaxel is safe, well-tolerated, and active. The recommended phase II dose is gemcitabine 1000 mg/m² and paclitaxel 150 mg/m² on days one and eight every 21 days. The antitumor activity observed with this regimen warrants further investigation.     

Phase II study of cisplatin, epirubicin, UFT, and leucovorin (PELUF) as first-line chemotherapy in metastatic gastric cancer

More than two-thirds of patients with gastric cancer present with metastatic disease and their curative options are limited. This phase II study assessed the efficacy and tolerability of cisplatin, epirubicin, tegafur-uracil (UFT) and leucovorin in patients with metastatic gastric cancer (MGC). Thirty-nine patients with previously untreated metastatic or unresectable gastric cancer received intravenous cisplatin 60 mg/m² and epirubicin 50 mg/m² on day 1 of a 28-day cycle; UFT 300 mg/m² was administered with oral leucovorin 30 mg/day in divided doses on days 1-22, followed by a 7-day rest. Two patients achieved a complete response, 13 had a partial response (overall response rate 38%; 95% confidence interval [CI] 24-52%) and 16 patients (41%) had stable disease. Median time to progression was 6.5 months (95% CI 5.5-7.5 months); overall survival was 9.5 months (95% CI 8.5-13.5 months). Grade 3/4 neutropenia, anemia, and thrombocytopenia occurred in 20%, 8%, and 3% of patients, respectively; two patients experienced febrile neutropenia. Grade 3 diarrhea occurred in three patients. The combination of cisplatin, epirubicin, UFT, and leucovorin has significant activity and tolerable toxicities in patients with MGC and represents a convenient treatment option for these patients.     

A dose-escalation study of irinotecan (CPT-11) in combination with cisplatin in patients with advanced non-small cell lung cancer previously treated with a docetaxel-based front line chemotherapy

Purpose: A phase I study was conducted to determine the maximum-tolerated dose (MTD) and the dose-limiting toxicities (DLTs) of a CPT-11 plus cisplatin combination as salvage treatment in patients with advanced non-small cell lung cancer (NSCLC). Patients and methods: Twenty-two patients with histologically confirmed NSCLC, who had failed taxotere-based front-line chemotherapy, were enrolled. The patients’ median age was 61 years, 19 (86%) were male, and 17 (77%) had a performance status (World Health Organization (WHO)) 0–1. CPT-11 was administered as a 60-min i.v. infusion at a fixed dose of 100 mg/m² on day 1 and at escalating doses on day 8, starting from 100 mg/m² with increments of 10 mg/m² ; cisplatin was administered at a fixed dose of 80 mg/m² on day 8, 2 h after CPT-11 administration. Treatment was repeated every 3 weeks. Results: At the dose of CPT-11 120 mg/m² , three out of four enrolled patients presented DLTs (grade 4 neutropenia, febrile neutropenia and delayed diarrhea); the addition of G-CSF at this level did not permit further dose-escalation. Grade 3/4 neutropenia was observed in 12 (18%) cycles, febrile neutropenia in four (6%), and grade 3/4 thrombocytopenia in four (6%). Grade 3/4 diarrhea was seen in six (29%) patients, and grade 2/3 nausea and vomiting in 12 (57%). Neurotoxicity grade 2 was observed in six (29%) patients and grade 3 in one (5%). Other toxicities were mild. The MTD was CPT-11 100 mg/m² on day 1 and 110 mg/m² on day 8 in combination with CDDP 80 mg/m² on day 8. Among 12 patients evaluable for response, partial response was achieved in two (16.7%) patients and stable disease in five (41.7%). Conclusion: The combination of CPT-11 and cisplatin has substantial but manageable toxicity and marginal activity as salvage treatment of patients with NSCLC who have failed taxotere-based front-line chemotherapy; further investigation is warranted to define its precise role in the second-line setting.     

A phase III study of adjuvant chemotherapy in advanced nasopharyngeal carcinoma patients

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, M₀ (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/m² cisplatin, 2,200 mg/m² 5-fluorouracil, and 120 mg/m² 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 (≥ Grade 3) occurred in 17 out of 819 (2.1%) cycles of weekly chemotherapy. No patient developed moderate to severe mucositis (≥ Grade 3).

We conclude that adjuvant chemotherapy after RT for patients with advanced NPC has no benefit for overall survival or relapse-free survival.     

Results of A trial with topotecan dose escalation and concurrent thoracic radiation therapy for locally advanced, inoperable nonsmall cell lung cancer

: To conduct a dose escalation clinical study with topotecan and concurrent standard dose thoracic irradiation to assess its feasibility and toxicity in the treatment of patients with locally advanced, inoperable nonsmall cell lung cancer (NSCLCA).

: Between April 1993 and August 1994, 12 patients with inoperable, loco-regionally advanced NSCLCA were entered in a prospective dose escalation trial and assigned to receive concurrent thoracic radiotherapy and topotecan. Patients received thoracic irradiation to a total tumor dose of 60 Gy in 30 fractions. Initial fields were to encompass the gross disease plus the mediastinum. Topotecan was delivered by bolus injection days 1 through 5, and days 22 through 26, beginning on the same day as the radiation therapy. The initial dose level was 0.5 mg/m². Two additional dose levels of 0.75 mg/m² and 1.0 mg/m² were tested.

: Six patients were accessioned to the 0.5 mg/m² dose level, three patients to the 0.75 mg/m² dose level, and three patients to the 1.0 mg/m² dose level. At the 0.5 mg/m² dose level, zero of six patients had ≥Grade 4 hematologic toxicity. One of the six had Grade 3 esophagitis. At the 0.75 mg/m² dose level, two of three patients had ≥Grade 3 nonhematologic toxicity including anorexia, fatigue, nausea, vomiting, and weakness; zero patients experienced ≥Grade 4 hematologic toxicity. At the 1.0 mg/m² dose level one of three patients had ≥Grade 3 esophagitis, and two of three patients experienced Grade 4 neutropenia. With a follow-up of 12 to 24 months, two patients are alive and free of disease, three patients are alive with disease (two with distant metastasis, one with local disease and distant metastasis), and the remaining seven patients are dead of disease.

: The combination of topotecan and thoracic radiotherapy for nonsmall lung cancer, in the manner given by this protocol, could be safely given at a dose level of only 0.5 mg/m² days 1 to 5 and 22 to 26 with 60 Gy of external beam radiotherapy. Higher doses of topotecan were associated with high hematologic and gastrointestinal toxicity. Distant metastasis was the primary pattern of failure.     

Phase I-II study of gemcitabine and paclitaxel in pretreated patients with stage IIIB-IV non-small cell lung cancer

Gemcitabine and paclitaxel are among the most active new agents in non-small cell lung cancer (NSCLC) and are worth considering for second-line chemotherapy. In this phase I–II study, we combined gemcitabine and paclitaxel for second-line treatment of advanced NSCLC. Gemcitabine doses were kept fixed at 1000 mg/m² on day 1 and 8, and paclitaxel doses were escalated from 90 mg/m² on day 1 of the 21-day cycle. Thirty-seven patients were treated at six different dose levels. Grade 4 neutropenia was dose-limiting toxicity (DLT), since it occurred in two out of six patients treated at paclitaxel 240 mg/m²; the paclitaxel dose level just below (210 mg/m²) was selected for phase II evaluation. Non-hematologic toxicity was mild. One complete response (CR) (3%) and 13 partial responses (PR) (36%) were observed in 36 evaluable patients for an overall response rate of 39% (95% C.I., 23–57%). Median duration of response was 35 weeks (range, 8–102). All of the observed objective responses occurred in the 19 patients who had previously responded to the first-line therapy. Median survival was 40 weeks (range, 8–108 weeks). The combination of gemcitabine and paclitaxel is a feasible, well-tolerated, and active scheme for second-line treatment of advanced NSCLC; further evaluation, at least in selected patients, such as those previously responding to first-line chemotherapy, is definitely warranted.     

Phase I study of twice-weekly gemcitabine and concomitant external-beam radiotherapy in patients with adenocarcinoma of the pancreas

To determine the maximum tolerated dose and dose-limiting toxicity associated with twice-weekly gemcitabine and concomitant external-beam radiotherapy in patients with adenocarcinoma of the pancreas.

Twenty-one patients with biopsy-proven adenocarcinoma of the pancreas were treated with external-beam radiotherapy to a dose of 50.4 Gy in 28 fractions, concurrent with gemcitabine, infused over 30 min before irradiation on a Monday and Thursday schedule. The dose of gemcitabine was escalated in 5 cohorts of 3–6 patients each. Initial gemcitabine dose was 10 mg/m², with dose escalation until dose-limiting toxicity was observed.

The maximum tolerated dose of gemcitabine was 50 mg/m², when given in a twice-weekly schedule with radiation. Dose-limiting toxicity was seen in 2 patients at 60 mg/m², and consisted of severe upper gastrointestinal bleeding approximately 1 month after completion of treatment. Six patients had radiographic evidence of response to treatment, and 5 of these underwent complete surgical resection. Three patients who underwent complete resection had been deemed to have unresectable tumors before enrollment on trial. Four patients are alive, including 2 without evidence of disease more than 1 year after resection.

The combination of external-beam radiation and twice-weekly gemcitabine at a dose of 50 mg/m² is well tolerated and shows promising activity for the treatment of pancreatic cancer. Our data suggest a higher maximum tolerated dose and different dose-limiting toxicity than previously reported. Further investigation of this regimen is warranted.     

局部晚期鼻咽癌洛铂单周方案同期放疗初探

目的 探讨局部晚期鼻咽癌洛铂单药单周方案同期放疗中洛铂最大耐受剂量(MTD)。方法 选择18例Ⅲ-ⅣA期鼻咽癌初治患者,采用根治性IMRT同时进行洛铂剂量递增试验。洛铂初始剂量10 mg/m²,组间递增剂量为5 mg/m²,每个剂量组至少3位受试者。如无剂量限制性毒性反应则进入下一剂量组直至MTD,定期评价疗效及不良反应。结果 10、15 mg/m²剂量组各3例,20、25 mg/m²剂量组6例。25mg/m²组出现2例剂量限制性毒性反应,因此MTD确定为20 mg/m²。患者治疗结束后3个月,鼻咽部肿瘤和颈部阳性淋巴结临床缓解率为100%。主要毒性反应为骨髓抑制。结论 洛铂单药周方案同期放化疗治疗局部晚期鼻咽癌的MTD为20mg/m²,该方案疗效可靠安全性较好,值得开展进一步临床研究。     

局部晚期鼻咽癌洛铂单周方案同期放疗初探

目的 探讨局部晚期鼻咽癌洛铂单药单周方案同期放疗中洛铂最大耐受剂量(MTD)。方法 选择18例Ⅲ-ⅣA期鼻咽癌初治患者,采用根治性IMRT同时进行洛铂剂量递增试验。洛铂初始剂量10 mg/m²,组间递增剂量为5 mg/m²,每个剂量组至少3位受试者。如无剂量限制性毒性反应则进入下一剂量组直至MTD,定期评价疗效及不良反应。结果 10、15 mg/m²剂量组各3例,20、25 mg/m²剂量组6例。25mg/m²组出现2例剂量限制性毒性反应,因此MTD确定为20 mg/m²。患者治疗结束后3个月,鼻咽部肿瘤和颈部阳性淋巴结临床缓解率为100%。主要毒性反应为骨髓抑制。结论 洛铂单药周方案同期放化疗治疗局部晚期鼻咽癌的MTD为20mg/m²,该方案疗效可靠安全性较好,值得开展进一步临床研究。     

Phase I Study of Sequential Administration of Topotecan and 5-Fluorouracil in Patients with Advanced Malignancies

Topotecan is a topoisomerase-I inhibitor, a drug that stabilizes a covalent complex of enzymes and causes strand cleavage of DNA. 5-Fluorouracil (5FU) is an antimetabolite that interferes with DNA synthesis. Preclinical studies using human cancer cell line models have shown potential therapeutic synergy between these two drugs by showing the maximum cytolytic effect using sequential 5FU followed by topotecan. In the current study, 5FU was used at a fixed dose of 375 mg/m² given intravenously for five consecutive days on a 28 day cycle. Topotecan was dose-escalated in cohorts of patients from 0.5 to 1.0 mg/m² given intravenously for 5 days after the 5FU dose. Eleven patients were entered at different dose levels. Both hematological and gastrointestinal toxicity were dose limiting. Diarrhea was the dose-limiting toxicity at the dose of 0.75 mg/m² of topotecan. Two cases of grade 4 neutropenia were also observed at this dose level. One patient with small cell lung cancer had a complete response, while one patient with metastatic colorectal cancer had a partial remission. Three other patients had stable disease, lasting between 6 and 8 months. Overall, the regimen was well tolerated. A phase II study using a dose of 5FU at 375 mg/m² followed by topotecan at 0.75 mg/m² intravenously over 5 days every 28 days is recommended.     

恩度联合化疗治疗转移性鼻咽癌的Ⅱ期临床研究

  目的  评估恩度联合化疗治疗转移性鼻咽癌的近期疗效和安全性。  方法  对30例影像学、细胞学或病理诊断转移性鼻咽癌患者进行化疗,初治患者采用顺铂+氟尿嘧啶方案,非初治患者采用吉西他滨+顺铂方案,化疗同时给予恩度1次/d,静滴,共14d。治疗期间监测血常规、生化、尿常规、血压、心电图等指标,化疗1次/3周,第2个疗程化疗后4周评估近期疗效并进行统计分析。疗效评估参照RECIST标准,主要不良反应评估参照美国国立癌症中心的常见毒性标准（NCI-CTC-AE 3.0版）。  结果  30例患者均完成治疗,其中CR 4例,PR 22例,SD 3例,PD 1例,临床获益率96.7%,客观反应率86.7%。3级以上不良反应主要有粒细胞减少、血小板降低和1例左心室舒张功能不全。所有患者经相应治疗后不良反应均得到缓解。  结论  恩度联合化疗治疗转移性鼻咽癌近期疗效和耐受性良好。值得进一步开展临床研究评估生存受益。      

A Phase I Study of Escalating Interferon Alpha-2A Combined with 5-Fluorouracil and Leucovorin in Patients with Gastrointestinal Malignancies

On the basis of preclinical data showing synergy between 5-fluorouracil (5-FU), leucovorin (LV) and IFN-alpha-2a, a phase I study was carried out to determine the maximum tolerable dose (MTD) of IFN-alpha-2a with this combination in patients with gastrointestinal malignancies. The treatment consisted of 370 mg/m² 5-FU and 200 mg/m², LV on days 1 to 5, and IFN-alpha-2a on days 1 to 5 of the first week of chemotherapy and on days 1, 3, 5 of each subsequent week, on a 28-day cycle. Six patients with colorectal, 3 with pancreas, 2 with oesophagus, 2 with hepatocellular and one with gastric cancer were treated. At level III (5 × lo⁶ U/m²) all patients experienced grade 3 or 4 toxicity during the first 56 days of treatment and the MTD was declared level II. Grade 3 toxicity comprised of anorexia, mucositis, diarrhoea, and fatigue; in one instance, grade 4 neutropenia occurred. Ten patients were evaluable for response, one patient with an oesophageal cancer had a minor response and one patient with rectal cancer and liver metastases had a radiological complete response lasting 3 months. The recommended dose for this schedule in phase TI studies is 5-FU 370 mg/m², LV 200 mg/m², and IFN-alpha-2a 4 × 10⁶ U/m².