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.     

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.     

局部晚期胃癌术后卡培他滨同期调强放疗的Ⅰ期临床研究

目的 观察局部晚期胃癌术后卡培他滨同期调强放疗(IMRT)中,卡培他滨的最大耐受剂量(MTD)和剂量限制性毒性(DLT)。方法 入组标准为接受根治术(R₀切除)或非根治术(R₁、R₂切除),术后病理证实为T_xN (+) M₀期的近端或远端胃癌患者。共18例患者入组,其中R₀术12例、R₁术2例、R₂术4例。放疗采用IMRT技术,R₀术后总剂量45 Gy,1.8 Gy/次,5 次/周。R₁或R₂术后,对有肉眼或镜下肿瘤残存部位进行局部加量10.8 Gy分6次。卡培他滨剂量水平分5级,分别为625 mg/m²(Ⅰ级)、700 mg/m²(Ⅱ级)、800 mg/m²(Ⅲ级)、900 mg/m²(Ⅳ级)、1000 mg/m²(Ⅴ级),口服2 次/d。结果 最常见1~3级的不良反应为白细胞减少(89%)、食欲下降(83%)和恶心(83%)。Ⅰ级中1例出现3级食欲下降、恶心和4级呕吐。Ⅱ级中1例出现3级食欲下降和恶心。Ⅲ级时2例分别出现4级中性粒细胞减少和3级放射性食管炎。结论 局部晚期胃癌术后卡培他滨同期IMRT的MTD为800 mg/m²,2 次/d,DLT为恶心、呕吐、食欲下降、中性粒细胞减少和放射性食管炎。     

A Phase I trial of weekly docetaxel and topotecan for solid tumors

Background/Aims. Topotecan and docetaxel are active agents in the treatment of various malignant diseases. Both drugs cause dose-limiting hematologic toxicity. This study defines the maximum tolerated dose (MTD) and dose-limiting toxicity of weekly topotecan when administered in combination with docetaxel 25 mg/m² given day 1, 8,15 every 28 days. Methods. Thirteen patients were enrolled. Median age was 62 years. Majority of the patients had lung cancer. Results. The maximum tolerated dose was docetaxel 25 mg/m² and topotecan 3 mg/m² administered weekly. Dose-limiting toxicity was febrile neutropenia. Eight patients developed at least grade 3 neutropenia in all cycles. Non-hematologic toxicities were mild. No objective responses were noted. Two patients with non-small cell lung cancer had stable disease as a best response. Conclusion. Combination docetaxel and topotecan given weekly is tolerable. The recommended phase II dose is docetaxel 25 mg/m² and topotecan 3 mg/m² day 1, 8, 15 every 28 days.     

A phase I trial of docetaxel based induction and concomitant chemotherapy in patients with locally advanced head and neck cancer

The purpose of this study was to determine the maximum tolerated dose (MTD) of docetaxel based induction and concomitant chemoradiotherapy (CRT) after using the FHX platform (5 = 5-FU, H = hydroxyurea, X = Radiation). Patients with Stage III/IV locally advanced HNSCC were enrolled. Induction chemotherapy (carboplatin/docetaxel) was followed by 5 cycles of concomitant docetaxel based CRT. No DLTs were observed in dose levels 1/2 for induction and CRT. Dose level 2 was expanded. The overall survival CR rate after CRT was 79 percent. Median overall (OS) has not been reached and 2-year OS is 80.7 percent. The recommended Phase II dose of docetaxel with FHX CRT is 25 mg/m² and 35 mg/m² in combination with carboplatin induction (AUC = 6).     

早期宫颈癌术后每周紫杉醇+顺铂同步3DCRT的Ⅰ期临床研究

目的 明确中国人每周紫杉醇和顺铂同步盆腔放疗早期宫颈癌术后患者的MTD。方法 顺序选择有高中危因素的早期宫颈癌术后患者25例,ECOG≤2。盆腔采用6、10 MV X线4个野3DCRT,照射剂量为40 Gy分20次后予盆腔中央挡铅,宫旁加量10~20 Gy分5~10次;¹⁹²Ir高剂量率腔内照射,参考点为阴道黏膜下0.5 cm,处方剂量为5 Gy/次共2~4次。化疗起始剂量为每周紫杉醇 10 mg/m²、顺铂 20 mg/m²,共6个周期。利用3+3设计方法,每3例患者进行剂量递增直至达到DLT水平。结果 入组患者均在7周内完成外照射和腔内照射。第7剂量组4例患者中2例4周期后出现DLT即3级腹泻。3、4级血液学反应主要为白细胞、中性粒细胞减少,主要发生在4~6周期化疗后。第6剂量组1例出现4级白细胞、中性粒细胞减少,但额外增加的3例未出现4级反应。同步化疗未延迟治疗时间。25例患者中22例完成了6周期化疗。中位随访时间59.5个月,3例患者死于复发转移,1例死于呼吸衰竭。结论 早期宫颈癌术后盆腔照射联合每周紫杉醇和顺铂的同步放化疗安全、耐受性好。中国人的MTD为6周期的每周顺铂35 mg/m²和紫杉醇30 mg/m²。     

Phase I clinical trial of topotecan and pegylated liposomal doxorubicin

Background: The objective of this study was to determine the feasibility and maximum tolerated dose (MTD) of combination topotecan and pegylated liposomal doxorubicin (PLD) administered in 4- or 3-week cycles in patients with advanced or refractory solid tumors. Patients and Methods: Patients were treated with intravenous topotecan (0.75-1.25 mg/m²) for 3 days followed by PLD (25-40 mg/m²) on Day 4. The following dose combinations (topotecan/PLD, mg/m²) were explored: 0.75/40, 1.0/40, and 1.25/40 every 28 days; and 1.0/25 and 1.0/30 every 21 days. Results: Thirty-two patients were enrolled, and all had received prior chemotherapy. Most (84 percent) patients had ovarian cancer. A total of 157 cycles (median, 4 cycles; range, 1-19 cycles) of chemotherapy were administered. Dose-limiting toxicities were Grade 4 neutropenia and death at dose level 3 (1.25/40 mg/m² every 28 days), and neutropenic fever, Grade 3 stomatitis, and Grade 3 peripheral neuropathy (all in one patient) at dose level 5 (1/30 mg/m² every 21 days). Myelosuppression was the most common serious toxicity. Twenty-six patients were evaluable for response and 7 (27 percent) had partial responses. All responses were seen in patients with ovarian cancer. Conclusions: This combination is feasible and well tolerated; encouraging activity was observed in heavily pretreated patients with ovarian cancer. The recommended regimens for a Phase II study are topotecan 1.0 mg/m² on Days 1-3 followed by PLD 40 mg/m² on Day 4 of a 28-day cycle, and topotecan 1.0 mg/m² on Days 1-3 and PLD 30 mg/m² on Day 4 of a 21-day cycle.     

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.     

洛铂联合固定剂量多西紫杉醇二线及以上治疗晚期实体肿瘤的剂量递增研究

背景与目的：恶性肿瘤一线化疗后多出现复发或转移,需要二线及以上治疗。本研究旨在确定洛铂联合固定剂量多西紫杉醇治疗化疗后进展的实体肿瘤时洛铂的最大耐受剂量(maximum-tolerated dose,MTD),并评价其不良反应。方法：应用改良的Fibonacci法进行洛铂剂量递增,固定多西紫杉醇剂量为60 mg/m²,洛铂初始剂量为30 mg/m²,组间递增剂量为5 mg/m²,每21天重复。每组至少3例,如1个剂量组中3例均无剂量限制性毒性(dose-limiting toxicity,DLT)出现,则进入下1个剂量组,直至出现DLT,DLT的低一剂量水平即为MTD。结果：17例患者共完成58个周期化疗,进行3个剂量组的研究(洛铂分别为30、35、40 mg/m²),完全缓解(complete response,CR)0例,部分缓解(partial response,PR)1例,疾病稳定(stable disease,SD)10例,疾病进展(progression disease,PD)3例;有效率(response rate,RR,CR+PR)为7.1%(1/14),疾病控制率(disease control rate,DCR,CR+PR+SD)为78.6%(11/14)。主要不良反应为白细胞下降,3例出现DLT,其中2例发生在洛铂40 mg/m²组。确定洛铂35 mg/m²组为MTD。结论：本组洛铂联合固定剂量多西紫杉醇的MTD为35 mg/m²,其不良反应可耐受。     

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.     

Toxicity of a 24-hour infusion of gemcitabine in biliary tract and pancreatic cancer: a pilot study

The antitumor activity of gemcitabine is not dose-response related but schedule-dependent. Based on the results of a published phase I study in patients with non-small-cell lung cancer we started a pilot study of a 24-hr infusion of gemcitabine in patients with adenocarcinoma of the pancreas and biliary tract cancer. Twenty-five patients were enrolled and received a 24-hr infusion of gemcitabine once weekly on three consecutive out of 4 weeks. Dose levels of gemcitabine ranged from 100 to 150 mg/m². One of 13 chemotherapy-naive patients had a partial response. Dose-limiting toxicity (DLT) was thrombocytopenia in pretreated patients and neutropenia in chemotherapy-naive patients. Other toxicities were oral mucositis, fever, flu-like symptoms, and asthenia. Maximum tolerated dose (MTD), especially in pretreated patients, was 100 mg/m².     

Phase I study of CT-2103, a polymer-conjugated paclitaxel, and carboplatin in patients with advanced solid tumors

Purpose: The primary objective of this study was to determine the maximum tolerated dose (MTD) of CT-2103 (poly L-glutamic acid-paclitaxel) in combination with carboplatin in patients with histologically proven solid tumors that were either refractory to conventional treatment or for which no conventional therapy was available. Patients and Methods: Twenty-two adult patients with advanced solid tumors were treated in this dose escalation study. Patients were treated every 21 days with CT-2103 at 175, 210, 225, or 250 mg/m² (doses expressed as units of conjugated-paclitaxel) via 10-20 minute intravenous (IV) infusion, followed one hour later with carboplatin administered at AUC 5 or 6 via 30 minute IV infusion. No prophylaxis for hypersensitivity was administered with initial treatment. Doses were administered every 21 days until progressive disease or dose-limiting toxicity (DLT) was observed. Toxicity was evaluated using NCI Common Toxicity Criteria for Adverse Events v2.0 (CTCAE v2.0); response to treatment was evaluated using Response Criteria in Solid Tumors (RECIST). Results: The MTD was determined to be 225 mg/m². DLTs observed at 250 mg/m² were neutropenia and thrombocytopenia. No hypersensitivity reactions were observed. Three patients achieved partial responses (PR). Fifteen patients received at least 3 cycles of treatment without observation of progressive disease. Median survival time was 5.9 months. Patients that demonstrated partial responses were all ovarian cancer patients that had previously failed paclitaxel therapy. The only Grade 4, nonhematologic treatment-related toxicity was febrile neutropenia. Grade 4 neutropenia (9 patients) was observed across all dose groups. Twelve patients developed thrombocytopenia (Grade 3/4) while receiving combination therapy. All had resolution of thrombocytopenia with discontinuation of carboplatin, suggesting that carboplatin, and not CT-2103, contributed mainly to platelet toxicity. Conclusion: CT-2103 administered at 225 mg/m² every 21 days in combination with carboplatin administered at AUC 6 has a manageable safety profile in patients with solid tumors; further clinical investigation is recommended, especially in patients with ovarian or non-small cell lung cancer.     

Phase I study of Doxil and vinorelbine in patients with advanced malignancies

Introduction. This study was designed to define the maximum tolerated dose of pegylated liposomal doxorubicin (Doxil®) and multiday vinorelbine (VNB), without and with prophylactic filgrastim, and to identify antineoplastic effect. Patients and Methods: Patients with resistant cancers were treated with Doxil 50 mg/m² every four weeks, and with VNB 15 mg/m² on the same day. The VNB dose escalations were accomplished in subsequent patient cohorts by adding VNB doses on consecutive days. When the maximum tolerated dose (MTD) of VNB with Doxil was defined, prophylactic filgrastim was added to define a second MTD. Results. Of 29 patients entered, two had early adverse events, and 27 received at least one full cycle with at least one month follow-up. The MTD of VNB, combined with Doxil 50 mg/m², was 15 mg/m² on day 1, with neutropenia as the dose-limiting toxicity. With prophylactic filgrastim, the MTD was15 mg/m² daily for two days, with neutropenia and stomatitis as dose-limiting toxicities. Palmar plantar erythrodysesthesia occurred frequently, usually after the third cycle. Objective responses were documented in six patients, all of whom received multiday VNB. Conclusion. Doxil 50 mg/m² on day 1 of a 28-day cycle can be safely combined with VNB 15 mg/m2 day 1, or with VNB 15 mg/m² days 1 and 2 with filgrastim prophylaxis. Antineoplastic activity was observed in this heavily pretreated population. Future studies of Doxil 35-40 mg/m² with multiday VNB may be worthwhile, especially in metastatic breast cancer.     

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 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.     

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.     

Paclitaxel and gemcitabine, as first-line chemotherapy, combined with trastuzumab in patients with advanced breast cancer: a phase II study conducted by the Hellenic Cooperative Oncology Group (HeCOG)

Purpose: Advanced breast cancer (ABC) is an incurable disease. Standard first-line treatment for patients with HER-2/neu overexpressing tumors includes the combination of the humanized monoclonal antibody trastuzumab with chemotherapy, mainly paclitaxel. This combination is the first to demonstrate a survival advantage in this group of patients. To improve on these results, we investigated a triplet, paclitaxel-gemcitabine-trastuzumab (TGH), in a phase II study. Patients and Methods: Patients with ABC were accrued to the study. Treatment consisted of paclitaxel 80 mg/m²/week, gemcitabine 1000 mg/m² every 2 weeks, and trastuzumab 4 mg/kg loading dose and then 2 mg/kg/week. Patients were treated on study for a total of 12 weeks. Response evaluation was performed at the end of the 12 weeks. Continuation of treatment beyond the 12 weeks was left to the discretion of the investigator. Primary study endpoint was response. Toxicity assessment and survival were secondary endpoints. Results: Between November 2000 and May 2002, 40 patients were accrued and 32 patients completed all 12 weeks of therapy. One patient died of septic shock during therapy. Grade III and IV neutropenia was seen in 12.5% of cases each. Grade III anemia was seen in two patients, and grade III and IV thrombocytopenia in three and two patients, respectively. Both paclitaxel and gemcitabine were delivered at 86% of the planned dose intensity. Six patients achieved a complete response (CR) and 15 a partial response for an overall response rate of 52.5%. An additional 25% demonstrated stable disease and 20% progressive disease. Median duration of response was 14 months. All six patients who achieved CR are still in CR for 6 to 19 months. After a median follow up of 12.2 months, 19 patients have progressed and 7 have died. Median time to progression is 13.7 months, whereas median survival has not been reached. Conclusion: TGH is a well-tolerated and effective regimen for the first-line treatment of ABC. Randomized comparison between paclitaxel, trastuzumab, and triplets are warranted.     

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.     

Gemcitabine and cisplatin in advanced nasopharyngeal carcinoma: a pilot study

A pilot study was performed to evaluate the efficacy and safety of gemcitabine and cisplatin combination in the treatment of patients with metastatic nasopharyngeal carcinoma (NPC). Eligible patients were those with metastatic NPC who had been treated with radiotherapy and cisplatin plus 5-fluorouracil chemotherapy. Cisplatin was given intravenously at the fixed dose of 30 mg/m² on days 1-3. Gemcitabine was intravenously administered over 30 min infusion with the dose escalated from 800 to 1200 mg/m² on days 1 and 8. The 3-week schedule defined a cycle of treatment. Fifteen patients were enrolled and assessed for the worst toxicities. For a total of 83 cycles, Grade 3-4 toxicity was 46.7% for neutropenia, 40.0% for thrombocytopenia, and 20.0% for anemia. Grade 3 nonhematologic toxicity was 13.3%. Fourteen patients were assessable for response. The overall response rate was 92.9%, with complete response in three patients (21.4%). Median survival was 10.2 months. Seven patients had lived more than one year, and two patients had lived more than 2 years. The recommended dose of gemcitabine was 1000 mg/m² on days 1 and 8 in each cycle. In conclusion, the present combination is well tolerated and highly active in the treatment of advanced NPC patients.     

A Phase I Trial of Combination Chemotherapy Employing Carboplatin, Vinca Alkaloids, with or without Bleomycin in Patients with Advanced Malignant Tumors

A Phase I trial of three carboplatin-based combination chemotherapy regimens was conducted. These included: carboplatin plus vindesine; carboplatin, vindesine, plus bleomycin; and, carboplatin plus vinblastine. Carboplatin was administered every 28 days as an intravenous bolus. The initial dose was 150 mg/m² and doses were escalated by 50 mg/m² in each successive group of patients. Vindesine was given at a dose of 3 mg/m² weekly for 5 doses, then every other week thereafter. Bleomycin, 10 units/m² IV bolus, was followed by 10 units/m²/day infusion for 4 days (3-7 and 31-35). Vinblastine was given at 5 mg/m² every other week. Doses of vindesine, vinblastine, and bleomycin were not escalated. The maximum tolerated dose (MTD) of the carboplatin, vindesine bleomycin regimens was reached at a carboplatin dose of 250 mg/m² and the MTD was influenced by the weekly vindesine in the initial 4 weeks of therapy. The MTD of the carboplatin and vinblastine regimen was reached at a carboplatin dose of 500 mg/m². Dose-limiting toxicity of all three regimens was leukopenia. Although nonhematological toxicity of the carboplatin and vinblastine regimen included peripheral neuropathy and emesis, therapy was easily administered in an outpatient setting. The recommended Phase II dose of carboplatin is 450 mg/m² in combination with vinblasrine at this dose and schedule for previously untreated patients. Twelve patients demonstrated major responses with the various regimens including 5 of 24 patients with adenocarcinoma of the upper gastrointestinal tract.