食管癌同期放化疗中奈达铂剂量递增临床Ⅰ期试验

[目的]探讨在食管癌同期放化疗中多西紫杉醇固定周剂量时奈达铂（NDP）的周最大耐受剂量（MTD）,并观察其不良反应。[方法]共入选20例初治食管鳞癌患者,采用三维适形放疗方法,DT：60～64Gy/30～32f,42～44d,同步化疗方案固定多西紫杉醇剂量20mg/w,共6w,NDP采用周剂量递增方法,起始剂量12mg/m2,递增剂量为6 mg/m2。剂量限制性毒性（DLT）定义为≥3级不良反应,出现DLT的前一剂量即为MTD。[结果]NDP 24mg/m2剂量水平时共有2例患者发生3～4级的DLT;NDP 18mg/m2、多西紫杉醇20mg即为MTD。主要不良反应为放射性食管炎、放射性肺炎、乏力和骨髓抑制。[结论]食管癌同步放化疗中固定多西紫杉醇20mg每周剂量时奈达铂每周最大耐受剂量为 18mg/m2。     

宫颈癌同期放化疗每周单药顺铂的Ⅰ和Ⅱ期临床试验

目的 探讨中晚期宫颈癌患者同期放化疗中适合中国人的顺铂单药化疗每周方案剂量。方法 Ⅰ_B2~Ⅳ_A期需放疗的宫颈癌患者为研究对象。Ⅰ期临床试验(15例)为剂量递增试验,顺铂剂量以20、25、30 、35、40 mg/m²逐渐递增(≥3例/剂量),40 mg/m²后不再增加剂量。依据Ⅰ期临床试验所得出的最大耐受剂量(40 mg/m²)进行Ⅱ期临床试验(36例)。盆腔放疗采用三维适形方法。结果 Ⅰ期临床试验剂量递增至顺铂40 mg/m²未出现限制性不良反应。Ⅱ期临床试验中住院的9例患者都完成了6周化疗,门诊治疗的27例患者18例完成6周化疗,19例完成5周化疗,25例完成4周化疗。所有患者都完成了放疗。主要不良反应为1、2级胃肠道反应与白细胞减少。     

A dose escalation study of concurrent chemoradiation therapy with nedaplatin for cervical cancer

Doses of nedaplatin (CDGP) were established for concurrent chemoradiation therapy (CCRT) for cervical cancer, and a collaborative dose escalation study involving 8 hospitals was conducted to investigate the safety and efficacy of this therapy. Radiotherapy was performed according to the standard treatment described in the Regulations of Cervical Carcinoma Treatment. CDGP at 80 mg/m2 as Level 1 or at 90 mg/m2 as Level 2 was administered on Days 1 and 29 of treatment. Dose-limiting toxicity (DLT) was observed in 1 of 6.patients receiving 80 mg/m2 of CDGP and in all 2 patients receiving 90 mg/m2 of CDGP; therefore, Level 2 was regarded as the maximum tolerated dose (MTD), and Level 1 as the recommended dose. DLT signs consisted of delayed improvement in the leukocyte count in 2 patients and anorexia in 1 patient, suggesting that delayed improvement in the leukocyte count is the main DLT of this combination therapy. The main side effects were digestive disorders such as nausea and anorexia and bone marrow suppression, such as leukopenia, neutropenia, and thrombopenia. Side effects in the Level 1 group were more mild than in the Level 2 group. The efficacy was PR or better in all patients. The CR rates were 60% (6/10) in the Level 1 group and 50% (1/2) in the Level 2 group; there was no marked difference between the two groups. These results suggest that CCRT involving administration of CDGP at 80 mg/m2 on Days 1 and 29 is safe and effective.     

Phase I dose-escalating study of raltitrexed ('Tomudex') and cisplatin in metastatic non-small cell lung cancer

BACKGROUND: The aim of this Phase I, dose-escalation study was to determine the maximum tolerated dose (MTD), recommended dose (RD), and dose-limiting toxicity (DLT) of a raltitrexed ('Tomudex') and cisplatin combination in patients with previously untreated, metastatic non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients received raltitrexed (15-min intravenous infusion), followed by cisplatin (1-h intravenous infusion), every 3 weeks at escalating dose levels. Results: In total, 21 patients entered the study. No DLT was observed up to dose level 4 (raltitrexed 3.0 mg/m(2) plus cisplatin 80 mg/m(2)), or in the first 3 patients who received dose level 5 (raltitrexed 3.5 mg/m(2) plus cisplatin 80 mg/m(2)). However, 1 patient, entered at dose level 6 (raltitrexed 4.0 mg/m(2) plus cisplatin 80 mg/m(2)) experienced severe toxicity (including grade 3 diarrhea), and no further patients were recruited at this level. Of 4 additional patients who received raltitrexed 3.5 mg/m(2) plus cisplatin 80 mg/m(2), 3 also experienced DLTs. The most common adverse events included nausea/vomiting, asthenia, diarrhea, and hematologic toxicities. Of 19 patients evaluated for response, 3 achieved a partial response, 13 had stable disease, and 3 progressed. CONCLUSIONS: The MTD is raltitrexed 3.5 mg/m(2) plus cisplatin 80 mg/m(2), and the RD for future studies is raltitrexed 3.0 mg/m(2) plus cisplatin 80 mg/m(2); DLTs were diarrhea and asthenia. The combination of raltitrexed and cisplatin shows clinical activity in patients with metastatic NSCLC.     

A dose-finding study of nedaplatin and cyclophosphamide for patients with gynecological malignancies.

BACKGROUND: Nedaplatin is a new analogue of cisplatin with similar efficacy but less renal toxicity. We investigated the appropriate dose of nedaplatin in combination with cyclophosphamide for patients with gynecological malignancies. METHODS: Nine patients (five with ovarian cancer and four with uterine cervical cancer) were studied. Three patients received 60 mg/m2 of nedaplatin combined with 500 mg/m2 of cyclophosphamide every 4 weeks. Another three patients were each administered 80 or 100 mg/m2 of nedaplatin with the same dose of cyclophosphamide. A total of 27 courses was given. RESULTS: No patient needed dose reduction due to myelosuppression and no severe adverse events were observed. CONCLUSIONS: Treatment with 100 mg/m2 of nedaplatin and 500 mg/m2 of cyclophosphamide is feasible for patients with gynecological malignancies. However, phase II studies are needed to clarify the efficacy of this combination chemotherapy.     

Phase I pharmacokinetic study of S-1 plus cisplatin in patients with advanced gastric carcinoma.

PURPOSE: The conversion rate of tegafur (a component of S-1) to fluorouracil (FU) differs in Asians and whites because of polymorphic differences in the CYP2A6 gene. S-1 with cisplatin is considered highly active in Japanese gastric cancer patients. Therefore, we initiated a phase I pharmacokinetic study of this combination in our gastric cancer patients. PATIENTS AND METHODS: Patients received cisplatin intravenously on day 1 and S-1 orally, twice daily, on days 1 to 21 every 28 days. At level 1, the S-1 dose was 25 mg/m2/dose (50 mg/m2/d), but it was increased by 5 mg/m2/dose for the next level. Cisplatin was administered at 75 mg/m2 (for levels 1 and 2) but was then reduced to 60 mg/m2 (level 1A). At every level, a cohort of three patients, which could be expanded to six patients, was studied. Maximum-tolerated dose (MTD) was determined based on the dose-limiting toxicity (DLT) in the first cycle. Patients with histologic proof of gastric adenocarcinoma and near-normal organ function were studied. RESULTS: Sixteen patients were enrolled. No DLTs occurred at level 1. However, DLTs occurred at levels 2 and 1A. The area under the curve for FU correlated significantly with DLT (P = .006) and grade 3 to 4 diarrhea (P = .004). Six partial responses were confirmed, including three at the MTD. CONCLUSION: At the established MTD of S-1 plus cisplatin, the S-1 dose (50 mg/m2/d for 21 days) is lower in our study than in the Japanese study (80 mg/m2/d for 21 days). A multi-institutional phase II study of this active combination is currently accruing patients.     

A pilot study of CPT-11 and cisplatin for ovarian clear cell adenocarcinoma

BACKGROUND: Ovarian clear cell adenocarcinoma is known to have poorer prognosis than ovarian serous cystadenocarcinoma. Cyclophosphamide plus cisplatin has been the standard therapy for ovarian cancer, but ovarian clear cell adenocarcinoma dose not respond to this therapy. The treatment for ovarian clear cell adenocarcinoma has not been established. We planned a pilot study of CPT-11 and cisplatin for the treatment of ovarian clear cell adenocarcinoma. METHODS: First, three patients were administered 70 mg/m2 of cisplatin intravenously on day 1 and 60 mg/m2 of CPT-11 intravenously on days 1, 8 and 15. Treatment was repeated every 4 weeks. Other patients were administered 75 mg/m2 of cisplatin intraperitoneally on day 1 and 60 mg/m2 of CPT-11 intravenously on days 1, 8 and 15. Treatment was repeated every 4 weeks. RESULTS: A total of 10 patients were entered in this study and a total of 43 courses were administered. 1 CR, 1 PR and 1 PD were observed in patients with measurable lesion. Grade 3 leukopenia was experienced in seven patients, grade 3 thrombocytopenia in two and grade 3 anemia in five. Grade 3 liver toxicity was observed in one patient and grade 3 diarrhea in one patient. No grade 4 toxicity was experienced. CONCLUSION: CPT-11 plus cisplatin is feasible and has efficacy for ovarian clear cell adenocarcinoma. This regimen should be explored in a phase II study.     

Phase I/II study of intravenous nedaplatin and intraarterial cisplatin with transcatheter arterial embolization for patients with locally advanced uterine cervical carcinoma

BACKGROUND: Nedaplatin, a platinum analog with less renal toxicity and similar efficacy for cervical carcinoma, recently has been shown to have a synergistic effect on cervical carcinoma lines in combination with cisplatin. To determine the clinical efficacy of this combination in patients with cervical carcinoma, the authors conducted a Phase I/II study of intravenous nedaplatin and intraarterial cisplatin combined with transcatheter arterial embolization (TAE). METHODS: Eligibility criteria were as follows: cervical carcinoma (Stages IB2-IV; International Federation of Gynecology and Obstetrics), 16-70 years of age, performance status between 0 and 2, and adequate bone marrow, renal, and hepatic function. Nedaplatin (40-70 mg/m2) was administered intravenously on Day 1 followed by intraarterial administration of cisplatin (70 mg/m2) on Day 3 via both uterine arteries by using the Seldinger method. This then was followed by TAE. This course of treatment was repeated every 3 weeks for 3 cycles. RESULTS: Patient data were as follows: age 37-68 (median, 55 years) and Stages IB2:4, IIA:3, IIB:2, IIIA:1, IIIB:3, IVA:2 carcinoma. The response to therapy was defined by magnetic resonance imaging as follows: partial response in 60% (9 of 15) of patients, complete response in 40% (6 of 15) of patients, and an overall response rate of 100% (95% confidence interval, 78-100%). Myelosuppression was manageable. Grade 3/4 renal toxicity was observed in 2 patients who received 70 mg/m2 of nedaplatin. Thirteen patients received radical hysterectomy, 1 patient received lymph node sampling, and 11 patients received adjuvant radiotherapy or chemotherapy. CONCLUSIONS: The maximum tolerable dose was 70 mg/m2 nedaplatin, and the dose-limiting toxicity was renal toxicity. The recommended dose was 60 mg/m2 nedaplatin intravenously followed by 70 mg/m2 cisplatin intraarterially. Intravenous nedaplatin followed by intraarterial cisplatin with TAE appears to be very effective for locally advanced cervical carcinoma.     

Phase I study of combination chemotherapy with 5-fluorouracil (5-FU) and nedaplatin (NDP): adverse effects and eecommended dose of NDP administered after 5-FU

When nedaplatin (NDP) was used as a single agent in the phase I study, the dose-limiting toxicity (DLT) was thrombocytopenia and the recommended dose (RD) was 100 mg/m2. However, the DLT, maximum tolerated dose (MTD) and RD of NDP used in combination with 5-fluorouracil remained unknown. Therefore, we performed this study to assess the DLT and RD of NDP administered after 5-fluorouracil (5-FU). In this study, 5-FU was administered to 38 patients at a fixed dose (700 mg/m2/d on days 1-5) and NDP administered on day 6 at an initial dose of 80 mg/m2, which was subsequently increased to 100, 120, 130, 140, 150, and 160 mg/m2. The DLT of NDP was leukopenia and its MTD and RD were 160 and 150 mg/m2, respectively. Concerning impairment of renal function, only two patients had a grade I increase in serum creatinine. There were 19 responders (50%, 19/38) achieving partial response or complete response in the evaluation of antitumor effect. The result of this study is notable in that administration of 5-FU before NDP allows the dose of NDP to be substantially increased.     

食管癌同期放化疗PF方案剂量递增试验

目的确定同期放化疗食管癌时顺铂（PDD）和氟尿嘧啶（5-Fu）方案的中国人最大耐受量（MTD）并观察其毒副反应.方法15例初治食管癌患者成为研究对象.全程常规分割照射,总剂量60Gy分30次.同期化疗采用改良Fibonacci法,从低剂量逐渐上升到高剂量,起始剂量为PDD37.5 mg/m^2第1天,5-Fu 500 mg/m^2第1～5天,28 d为1个周期,共4个周期.递增剂量为PDD7.5mg/m^2,5-Fu 100mg/m^2,每剂量组至少3例,如无剂量限制毒性（DLT）出现则进入下一剂量组,直至出现DLT,DLT的次一剂量即为MTD.结果DLT为3级放射性食管炎,发生于PDD 60mg/m^2,5-Fu700mg/m^2剂量水平;则其次一剂量PDD 52.5mg/m^2,5-Fu 700mg/m^2即为MTD.主要毒副反应为放射性食管炎、白细胞减少、恶心呕吐和厌食.结论同期放化疗食管癌PF方案的中国人最大耐受量为PDD 52.5 mg/m^2第1天,5-Fu 700 mg/m^2第1～5天,28 d为1个周期,共4个周期.     

Fractionated Scheme of Oral Vinorelbine as Single-Agent Therapy or in Combination With Cisplatin Concomitantly With Thoracic Radiotherapy in Stage III Non–Small-Cell Lung Cancer: Dose-Escalation Phase I Trial

IntroductionA dose-determination study was conducted in untreated stage III non–small-cell lung cancer to assess continuous exposure to fractionated oral vinorelbine (NVBo), a radiosensitizer, during the radiotherapy period, either alone (first cohort) or in combination with cisplatin (second cohort).Patients and MethodsThree patients with stage IIIAN2/IIIB were expected at each dose level, with 3 additional patients in case of dose-limiting toxicity (DLT). Concomitantly with a 60-Gy total dose of radiotherapy, NVBo was given from 60 mg up to 180 mg total dose per week split on days 1, 3, and 5. Once the maximum tolerated dose (MTD), defined as 2 DLTs in a dose level, was determined and the recommended dose of NVBo alone was established, the trial assessed its recommended dose in combination with cisplatin 80 mg/m² every 3 weeks.ResultsIn the first cohort, 26 patients were enrolled. MTD was 160 mg/wk; there were 3 cases of grade 3 esophagitis and 1 of grade 3 pneumonia as DLT out of 5 patients in this dose level. In the recommended dose level (150 mg/wk), only 1 of 6 patients experienced a DLT. In the second cohort, 11 patients received NVBo weekly doses from 130 mg to 150 mg with cisplatin. Only 2 patients received 150 mg/wk NVBo; the trial closed before MTD was determined. The confirmed response rates were 42% and 55% in the first and second cohort, respectively.ConclusionThe recommended dose of this fractionated NVBo scheme as single-agent therapy concomitantly with radiotherapy for 6 weeks is 50 mg on days 1, 3, and 5 (150 mg/wk); combined with cisplatin 80 mg/m² every 3 weeks, the dose should be 140 to 150 mg/wk adapted on hematology. The response rate is promising.     

Sequential chemo- and radiochemotherapy with weekly paclitaxel (Taxol) and 3D-conformal radiotherapy of stage III inoperable non-small cell lung cancer. Results of a dose escalation study

The purpose of this study was the determination of the maximum tolerable dose (MTD) of weekly paclitaxel (PX) in combination with 3D-conformal radiotherapy in non-small cell lung cancer (NSCLC) and the evaluation of side effects, patient outcome and tumor response. Thirty-eight patients with inoperable NSCLC, UICC-stage IIIA (n=14)/IIIB (n=24) received two cycles of induction chemotherapy with PX/carboplatin followed by combined radiochemotherapy (60 Gy/6 weeks) with weekly PX which was escalated in cohorts of four patients until dose limiting toxicity (DLT) was reached. Starting level was 40 mg/m(2). 3D-conformal radiotherapy was applied in all patients. Toxicity was determined by WHO criteria. Patients were followed-up 3-monthly. Thirty eight patients have entered the study, 34 patients are evaluable. DLT was esophagitis III degrees, requiring interruption of radiotherapy and was reached at the PX 70 mg/m(2). Two hypersensitivity reactions (50 mg/m(2)) and one leucopenia III degrees (60 mg/m(2)) were observed. Only one patient (60 mg/m(2), 50 Gy) completely aborted treatment. The pneumonitis rate was between 21 and 36% but showed no clear correlation with PX dose. Tumor response (PR and CR) defined by CT-scan 6 weeks following radiotherapy was 88% (30/34). The 1- and 2-year survival rate is 73% and 34%. We conclude that the MTD of weekly PX with 60 Gy normofractionated radiotherapy is 60 mg/m(2). The DLT is esophagitis. Response and survival data of this sequential/combined approach are promising. A minor increase of pulmonary toxicity of irradiation is suspected.     

Phase I study of the combination of gemcitabine and nedaplatin for treatment of previously untreated advanced non-small cell lung cancer

This trial was conducted to determine the maximum-tolerated dose (MTD), principal toxicity, and recommend dose for phase II study of the combination of gemcitabine and nedaplatin in patients with advanced non-small cell lung cancer (NSCLC). Patients with previously untreated NSCLC were eligible if they had a performance status of 0-2, were 75 years or younger, and had adequate organ function. The doses of gemcitabine (days 1, 8) and nedaplatin (day 1) studied were 800/60, 800/70, 800/80, 1000/80, and 1000/100 (mg/m(2)), repeated every 3 weeks. Toxicity could be assessed in all 21 patients enrolled, response could be assessed in 20 patients. The patients were 12 men and 9 women with a mean age of 69 years (range, 47-75 years). Four patients had stage IIIB disease and 17 patients had stage IV disease. The most common histologic type was adenocarcinoma. The MTD was not reached even at the highest doses. The most frequent toxic effects were thrombocytopenia and neutropenia: grade 3 or 4 thrombocytopenia was observed in 19% of patients, and grade 3 or 4 neutropenia in 24% of patients. Nonhematologic toxicities were mild. Grade 3 hepatic dysfunction occurred in 3 patients. Relatively few patients required dose modifications. The median dose-intensities were 91.5 and 93.1%, respectively, of the planned doses of gemcitabine and nedaplatin. The overall response rate was 35% (95% confidence interval, 15.4-59.2%). All responses were seen above level 3. The MTD was not reached even at the highest combination doses. We recommend doses of 1000 mg/m(2) of gemcitabine and 100 mg/m(2) of nedaplatin for phase II study. This combination chemotherapy is active and well tolerated and warrants phase II study.     

Phase I study of irinotecan and cisplatin with concurrent split-course radiotherapy in limited-disease small-cell lung cancer

We conducted a phase I study of irinotecan (CPT-11) and cisplatin with concurrent split-course radiotherapy in limited-disease small-cell lung cancer (LD-SCLC). This study aimed to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of this therapy. Four chemotherapy cycles of CPT-11 (days 1, 8 and 15) and cisplatin (day 1) were repeated every 28 days. Radiotherapy of 2 Gy/day commenced on day 2 of each chemotherapy cycle with 20 Gy administered from the first to the third cycles (a total of 60 Gy). 17 patients were enrolled at three dose levels (CPT-11/cisplatin: 40/60, 50/60 and 60/60 mg/m(2)), and 16 were evaluable for toxicity and outcome. 2 of 4 patients at 60/60 mg/m(2) refused continuation of therapy because of general fatigue, and the relative dose intensity of CPT-11 at 50/60 mg/m(2) was approximately 50%. These levels were considered as the MTD. Tumour responses included four complete responses (CR), 11 partial responses (PR) and one no change (NC), and the overall response rate was 93.8% (95% confidence interval: (CI) 71.7-98.9%). This combined modality is tolerable, and CPT-11/cisplatin of 40/60 mg/m(2) in this modality is recommended for phase II study.     

Phase I trial of outpatient weekly docetaxel, carboplatin and concurrent thoracic radiation therapy for stage III unresectable non-small-cell lung cancer: a Vanderbilt cancer center affiliate network (VCCAN) trial.

PURPOSE: Docetaxel, an active agent for non-small cell lung cancer (NSCLC), has demonstrated activity as a radiosensitizer in numerous pre-clinical studies. We conducted a phase I trial to determine the maximum-tolerated dose (MTD) and dose-limiting toxicities (DLT) of weekly Docetaxel, Carboplatin with concurrent thoracic radiation therapy (TRT) in patients with unresectable stage III NSCLC. PATIENTS AND METHODS: In this phase I clinical trial, Docetaxel was administered weekly as a 1-h intravenous infusion for 6 weeks with a starting dose of 20 mg/m(2). Docetaxel doses were escalated by 10 mg/m(2) increments in successive cohorts of three patients. DLT was defined as grade >or=3 nonhematologic and hematologic toxicity according to RTOG toxicity criteria. Once the DLT of Docetaxel alone was reached, weekly Carboplatin (AUC 2) was added at a DLT-2 dose of Docetaxel (two dose levels below that of dose limiting toxicity). Docetaxel doses were again escalated at 10 mg/m(2) increments in successive cohorts of three new patients to define further DLT and MTD of Docetaxel/Carboplatin with TRT. TRT was administered to the primary tumor and regional lymph nodes (40 Gy) followed by a boost to the tumor (20 Gy). RESULTS: Fifteen patients were entered onto this study with Docetaxel alone through three dose escalations (from 20 to 40 mg/m(2) weekly). The DLT of weekly Docetaxel/TRT was esophagitis and the MTD was 30 mg/m(2) per week for 6 weeks. Nine more patients were added with the Docetaxel/Carboplatin/TRT regimen. The DLT of weekly Docetaxel/Carboplatin with TRT was esophagitis and the MTD of Docetaxel was 20 mg/m(2) per week with weekly Carboplatin (AUC 2). There were 2 complete responses and 13 partial responses in 25 evaluable patients (RR 60%). CONCLUSIONS: This combination regimen has activity with manageable toxicity in patients with stage III NSCLC. A phase II study is planned to define activity.     

A phase I study of TS-1 and weekly cisplatin in patients with advanced gastric cancer

This is a phase I study to determine the maximum tolerated dose (MTD) and toxicity of a combination of TS-1 and weekly cisplatin (CDDP) in advanced gastric cancer patients. TS-1 was administered orally twice daily after meals, at a standard dose of 80 mg/m2. One course consisted of 21 days' consecutive administration followed by 14 days' rest. Cisplatin (CDDP) was injected intravenously on days 8, 15 and 22 using the following dose levels: dose level 1 20 mg/m2, dose level 2 25 mg/m2, and dose level 3 30 mg/m2. Twelve patients were entered in this trial. One of the 6 patients at dose level 3 had neutropenia NCI-CTC grade 3, while another patient at dose level 3 suffered from DLT (liver function grade 3. The maximal tolerable dose (MTD) was not reached using dose level 3. Partial responses were seen in 5 (62.5%) of 8 patients with evaluable lesions. At level 2 (25 mg/m2), the response rate was 100%. We recommended dose level 2 for phase II trials from the standpoint of toxicity and response rate.     

A phase I trial of intravenous melphalan, paclitaxel, and cisplatin plus granulocyte-colony stimulating factor in patients with suboptimal advanced epithelial ovarian carcinoma or peritoneal carcinoma

BACKGROUND: The primary purpose of this study was to establish the maximum tolerated dose (MTD) of intravenous melphalan in combination with paclitaxel and cisplatin plus granulocyte-colony stimulating factor (G-CSF) in patients with suboptimal advanced epithelial ovarian carcinoma or primary peritoneal carcinoma. METHODS: Patients with suboptimal (>2 cm residual tumor) Stage III or Stage IV epithelial ovarian carcinoma or peritoneal carcinoma were eligible for this Phase I study. In the first stage of the study, the doses of paclitaxel and cisplatin were fixed at 135 mg/m(2) and 75 mg/ m(2), respectively, and the dose of intravenous melphalan was escalated in consecutive cohorts of 3-6 patients depending on toxicity. The planned dose escalation levels of melphalan were 6 mg/m(2), 10 mg/m(2), and 14 mg/m(2). In the second stage of the study, the doses of cisplatin and melphalan were fixed at 75 mg/m(2) and the MTD level, respectively, and the dose of paclitaxel was escalated. The planned dose escalation levels of paclitaxel were 150 mg/m(2), 175 mg/m(2), 200 mg/m(2), 225 mg/m(2), and 250 mg/m(2). G-CSF was administered for 12-19 days with each cycle, and cycles were repeated every 4 weeks for a total of 6 cycles. Other end points included clinical or surgical response, progression free survival, and survival. RESULTS: Between January 1993 and May 1996, 34 women with untreated advanced stage epithelial ovarian carcinoma or primary peritoneal carcinoma were treated with 192 cycles of therapy. The MTD of melphalan was 10 mg/m(2), with the dose-limiting toxicity being thrombocytopenia. Paclitaxel was escalated to a dose level of 200 mg/m(2) with a toxicity rate of < 33%. The clinical response rate was 80% in 29 patients with measurable disease. Of 11 patients who underwent second-look surgery, 5 (45%) had a surgical pathologic complete response. The median progression free survival was 16.8 months and the median survival was 32.8 months. CONCLUSIONS: The combination of intravenous melphalan, paclitaxel, and cisplatin was found to have acceptable toxicity and good activity. A Phase II study of this combination appears to be warranted.     

Phase I study of weekly paclitaxel and liposomal doxorubicin in patients with advanced solid tumours

The aim of this study was to determine the maximum tolerated dose (MTD) and the dose-limiting toxicities (DLT) of a weekly administration of paclitaxel and pegylated liposomal doxorubicin (Caelyx; Schering Plough Pharmaceutical) in patients with advanced solid tumours. 19 pretreated patients with solid tumours received escalated doses of pegylated liposomal doxorubicin (6-12 mg/m(2)) as a 1-h intravenous (i.v.) infusion followed by a fixed dose of paclitaxel (80 mg/m(2)) weekly for 4 consecutive weeks in cycles of 6 weeks. DLT was defined as grade 4 neutropenia or thrombocytopenia, febrile neutropenia, grades 3 or 4 non-haematological toxicity or treatment delay due to unresolved toxicity during cycle 1. The MTD was reached at the dose of pegylated liposomal doxorubicin of 10 mg/m(2)/week and paclitaxel of 80 mg/m(2)/week. The DLTs were treatment delay due to grade 3 neutropenia and grade 3 diarrhoea. A total of 55 chemotherapy cycles were administered, and grades 3-4 neutropenia occurred in seven cycles (13%); the non-haematological toxicity was mild with grades 2/3 diarrhoea occurring in 4 (7%), grades 2-4 asthenia in 11 (20%) and grade 2 mucositis in 7 (13%) cycles. There was no case with more than a 10% LVEF decrease after a median of 3 (range 2-6) administered cycles/patients. One patient with breast cancer and 1 with ovarian cancer experienced a major partial response. The weekly administration of pegylated liposomal doxorubicin at the dose of 10 mg/m(2) in combination with paclitaxel at the dose of 80 mg/m(2) for 4 consecutive weeks, in cycles of 6 weeks which represent the recommended doses for further phase II studies, is a well tolerated regimen, which merits further evaluation in tumours known to be sensitive to taxanes and/or anthracyclines.     

Radiation therapy and concurrent fixed dose amifostine with escalating doses of twice-weekly gemcitabine in advanced pancreatic cancer.

PURPOSE: To determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of twice-weekly gemcitabine (TW-G) when administered in conjunction with fixed dose amifostine (A) during external radiotherapy (RT) in patients with advanced pancreatic cancer. METHODS AND MATERIALS: Ten patients with previously untreated, locally advanced, or asymptomatic-metastatic pancreatic adenocarcinoma were enrolled in this study. RT was delivered by using the standard four-field technique (1.8 Gy daily fractions, 45 Gy followed by a boost of 5.4 Gy, in 5-1/2 weeks). The starting dose of TW-G was 60 mg/m(2) (i.v., 30-min infusion), which is equal to the upper limit of previously reported MTD of TW-G when given without A during RT. A was given just before the TW-G, at a fixed dose of 340 mg/m(2) (i.v., rapid infusion). TW-G doses were escalated by 30-mg/m(2) increments in successive cohorts of 3 to 6 additional patients until DLT was observed. Toxicities were graded using the Radiation Therapy Oncology Group and National Cancer Institute Common Toxicity Criteria, version 2.0. RESULTS: In general, therapy was well tolerated in patients treated at the first two dose levels of 60 mg/m(2) and 90 mg/m(2). The DLT of TW-G given in conjunction with A during RT were neutropenia, thrombocytopenia, and nausea/vomiting at the dose level of 120 mg/m(2). Of the 10 patients eligible for a median follow-up of 10 months, 5 remain alive; 1 complete responder, 3 partial responders, and 1 with stable disease. CONCLUSION: A dose of TW-G at a level of 90 mg/m(2) produced tolerable toxicity and it may possess significant activity when delivered in conjunction with 340 mg/m(2) dose of A during RT of the upper abdomen. Due to the higher MTD of TW-G seen in our study, we consider that the A supplementation may optimize the therapeutic index of TW-G-based chemoradiotherapy protocols in patients with pancreatic carcinoma.     

A single-institute phase I/II trial combining nedaplatin dose escalation with a fixed dose of docetaxel for induction chemotherapy of oral squamous cell carcinoma

The purpose of this clinical trial was to assess the toxicity and efficacy of docetaxel plus nedaplatin induction chemotherapy in patients with locally advanced oral squamous cell carcinoma (OSCC). Twenty-one patients were enrolled in this phase I/II clinical study. The toxicities, response rates, and the maximum tolerated dose of nedaplatin that could be safely given preoperatively were assessed. Patients received escalating doses of nedaplatin (60, 70, 80, 90 mg/m²) combined with a fixed dose of docetaxel (60 mg/m²) on day one. Dose-limiting toxicity (DLT), grade 4 leukopenia lasting for two days or more, was seen in one patient at dose level 3; no other DLT was observed at any dose level. The overall response rate was 66.7%. The response rate was 100% at nedaplatin dose level 4, while that at dose level 1 was low (33.3%). Given these results, the recommended dose of nedaplatin in this regimen combined with fixed dose docetaxel (60 mg/m²) was determined to be 90 mg/m². Docetaxel 60 mg/m² plus nedaplatin 90 mg/m² induction chemotherapy can be recommended for patients with locally advanced oral squamous cell carcinoma. Based on these results, an early phase II clinical study using this dose level was conducted; docetaxel plus nedaplatin induction chemotherapy appears to be a useful regimen for the treatment of OSCC. A late phase II clinical study is warranted.