Phase I/II trial of docetaxel and carboplatin in previously untreated patients with advanced non-small-cell lung cancer

Background. This trial was conducted to determine the maximum tolerated dose (MTD) and principal toxicities of combinations of docetaxel and carboplatin administered every 3 weeks to patients with advanced non-small-cell lung cancer (NSCLC) previously untreated with chemotherapy, and to find suitable doses for phase II studies in Japanese subjects. Methods. Japanese patients with advanced NSCLC and performance status 0 to 2 according to the World Health Organization classification, but previously untreated with chemotherapy received docetaxel followed by carboplatin, each infused over a 1-h period. The carboplatin dose was based on the target area under the curve (AUC), using Calvert's formula. Dose levels studied were: docetaxel (mg/m²)/carboplatin AUC (mg/ml·min), 50/4, 60/4, and 60/5, repeated every 3 weeks. Granulocyte-colony stimulating factor (G-CSF) support was first used when dose-limiting toxicities (DLTs) were encountered. Results. Of 14 patients entered, 12 were assessable for toxicity and response. The MTD schedule was: docetaxel, 60 mg/m², with carboplatin, AUC 5 mg/ml·min (DLTs in 3 of 3 patients). The recommended dosage was: docetaxel, 60 mg/m², with carboplatin, AUC 4 mg/ml·min (DLTs in 2 of 6 patients). The main toxic effect was neutropenia, and any nonhematologic toxic effects were mild. No thrombocytopenia occurred. Six of the 12 patients (50%) showed responses; 4 of the 6 at the recommended doses. Conclusion. Docetaxel 60 mg/m², given over a 1-h period, followed by carboplatin, AUC 4 mg/ml·min, given over a 1-h period, is recommended for phase II studies in Japan. This combined chemotherapy has mild toxicity, except for neutropenia, and is useful and easy to administer. We therefore believe that phase II and phase III studies of this therapy would be well justified. Received: October 4, 1999 / Accepted: June 28, 2000     

Phase I study of second-line chemotherapy with docetaxel and carboplatin in advanced non-small-cell lung cancer

PURPOSE: Docetaxel and carboplatin have a broad spectrum of antitumor activity. We conducted a phase I study of docetaxel and carboplatin as second-line chemotherapy in previously treated non-small-cell lung cancer (NSCLC). This study aimed to determine the maximum tolerated dose (MTD) and the dose-limiting toxicities in this second-line combination chemotherapy. METHODS: Patients with advanced NSCLC were treated with escalating docetaxel doses in combination with a fixed-target area under the concentration-time curve (AUC) of 5 mg min/ml of carboplatin on day 1 of a 3-4-week cycle. The carboplatin dose was determined by multiplying the AUC by the clearance predicted using the Chatelut formula. The docetaxel dose was escalated from 40 mg/m2 to the MTD by 10 mg/m2 increments. RESULTS: A total of 16 patients previously treated with anticancer drugs were enrolled through three dose levels (40, 50 and 60 mg/m2 of docetaxel). All patients were assessable for toxicity and response. The MTD was docetaxel 60 mg/m2 with a carboplatin target AUC of 5 mg min/ml, and the dose-limiting toxicities in two of four patients were neutropenia and thrombocytopenia. Overall, neutropenia and thrombocytopenia of grade 3/4 occurred in eight patients (50%) and three patients (19%), respectively. Four patients (25%) and two patients (13%) experienced both grade 1 diarrhea and dermatitis, respectively. Allergic reactions, fluid retention, pneumonitis, neurotoxicity and mucositis were not observed. Of 16 patients, 5 showed an objective response (response rate 31%; 95% CI 14-56%). CONCLUSIONS: The combination of docetaxel and carboplatin is a feasible and well-tolerated second-line chemotherapy regimen in the treatment of NSCLC. Docetaxel 50 mg/m2 under the carboplatin target AUC of 5 mg x min/ml using the Chatelut formula was the recommended dose for phase II study.     

Intensive weekly chemotherapy with docetaxel, epirubicin and carboplatin with G-CSF support in patients with advanced gastric cancer

Chemotherapy is an established modality in the management of patients with advanced gastric cancer but the optimal regimen has not been defined yet. Platinum and the anthracyclines and more recently docetaxel have shown activity in this tumor. The primary objective of this phase II study was to assess the efficacy and safety of an intensified regimen of weekly docetaxel/epirubicin/carboplatin (DECb) with growth factor support in previously untreated patients with advanced gastric cancer. A total of 72 patients with measurable disease received docetaxel at a dose of 30 mg/m², epirubicin at a dose of 30 mg/m² and carboplatin to a target area under the curve (AUC) of 2, every week for 6 consecutive weeks followed by 2 weeks’ rest, with filgrastim support. Analysis was performed on an intention to treat basis. The main toxicity was hematologic with grade 3/4 neutropenia occurring in 35% of the patients. Other grade 3/4 toxicities included anemia (7%), thrombocytopenia (14%) and leucopenia (26%). The relative dose intensity of docetaxel and epirubicin was 62%. The overall response rate was 21%, the median time to tumor progression was 4.1 months and the median survival 7.3 months. Intensified weekly treatment with DECb has modest activity in the treatment of advanced gastric cancer. Myelotoxicity limits adequate drug delivery. Presented in part at the 41st American Society of Clinical Oncology Annual Meeting, Orlando, Florida, May 13–17, 2005.     

GM-CSF,carboplatin, doxorubicin: a phase I study

Dose intensification has the potential to increase the response frequency of chemosensitive tumors to chemotherapy. G-CSF and GM-CSF offer the possibility of dose-intensifying chemotherapy without prohibitive myelosuppression. A phase I study was undertaken to identify the maximum tolerated dose (MTD) of carboplatin that could be administered with a fixed dose of doxorubicin, 60 mg/m², administered every 28 days. Further escalation of the carboplatin dose was then attempted, with the concomitant addition of GM-CSF 10 mg/kg per day on days 1–21. We had 21 patients, 13 with prior therapy, who were eligible. In all, 60 courses of therapy were delivered, all with doxorubicin and with carboplatin doses of 250 mg/m², 325 mg/m² and 400 mg/m². At carboplatin 400 mg/m² and doxorubicin 60 mg/m², thrombocytopenia was dose limiting. The addition of GM-CSF did not allow further escalation. Of the 6 patients treated with carboplatin 400 mg/m², doxorubicin 60 mg/m², and GM-CSF, grade 4 granulocytopenia and thrombocytopenia were seen in 4 and 5 patients, respectively. The severity of thrombocytopenia was related to the calculated carboplatin AUC and also to baseline platelet count and prior therapy. In addition, the interaction of GM-CSF and chemotherapy, especially carboplatin-based, may be more complex than originally anticipated.This investigation was supported in part by the following PHS Cooperative Agreement grant numbers awarded by the National Cancer Institute, DHHS: CA-14028, CA-28862, CA-12213, CA-13612, CA-32102     

Carboplatin and docetaxel in advanced non-small-cell lung cancer: results of a multicenter phase II study

Background To evaluate the efficacy of carboplatin and docetaxel combination in patients with advanced non-small-cell lung cancer.Methods In a phase II study, patients with inoperable stage IIIB or stage IV non-small-cell lung cancer (ECOG performance status of 0 or 1) were treated with the combination of carboplatin AUC 5 mg/ml·min and docetaxel 80 mg/m² administered once every 3 weeks.Results A total of 45 patients were accrued to the study. The median age was 62 years and adenocarcinoma was the most common histology. Patients received a median of four cycles of chemotherapy. The objective response rate was 29% with a median survival of 11.9 months among evaluable patients. The 1-year survival rate was 47%. Febrile neutropenia (17%) was the most common hematological toxicity associated with the regimen whereas grade 3 fatigue (4%) was the major nonhematological toxicity.Conclusions The combination of carboplatin plus docetaxel is well tolerated and is effective for the treatment of patients with previously untreated advanced or metastatic non-small-cell lung cancer.This work was supported in part by Aventis Pharmaceuticals Inc.     

Sequence effect of docetaxel and carboplatin on toxicity, tumor response and pharmacokinetics in non-small-cell lung cancer patients: a phase I study of two sequences

Purpose To investigate sequence effects on toxicity, tumor response and pharmacokinetics of docetaxel and carboplatin, together with a determination of the maximum-tolerated dose (MTD) and recommended dose for each schedule.Patients and methods A total of 46 chemotherapy-naive patients with advanced non-small-cell lung cancer were randomized to receive docetaxel before (schedule A) or after (schedule B) carboplatin. The dose levels studied were [docetaxel (mg/m²)/carboplatin (mg×min/ml)] 50/5, 60/5, 60/6, 60/7, and 70/6. Treatment cycles were repeated every 3 or 4 weeks unless disease progression or undue toxicity occurred.Results Of the 46 patients, 44 were assessable for toxicity and received a total of 84 cycles. The major dose-limiting toxicity was neutropenia. When the docetaxel dose was 60 mg/m², the carboplatin MTD was deemed to be AUC 7 in both schedules. When the docetaxel dose was escalated to 70 mg/m², the carboplatin MTD was reached in schedule A, and the dose-limiting toxicity was not observed in schedule B. Tumor response was observed in 4 of 22 patients (18%) with schedule A and 8 of 19 (42%) with schedule B. Clearances of both drugs were not affected by sequence: 111.2±26.8 ml/min and 107.8±29.0 ml/min for carboplatin (P=0.69), and 26.7±8.3 l/h and 22.8±7.0 l/h for docetaxel (P=0.19) in schedules A and B, respectively.Conclusions Carboplatin AUC 6 followed by docetaxel 70 mg/m² was a favorable regimen for phase II study because of likely lower toxicity and a potentially higher response rate than the reverse sequence schedule. The mechanism of the sequence effects on toxicity and tumor response could not be explained by the pharmacokinetic interactions.Supported by grants from the Ministry of Health, Labor and Welfare, and the Ministry of Education, Culture, Sports, Science and Technology of Japan.     

A pilot study of docetaxel-carboplatin versus paclitaxel-carboplatin in Japanese patients with epithelial ovarian cancer

Background It has been reported that a docetaxel-carboplatin combination as first-line chemotherapy for ovarian cancer showed a level of progression-free survival similar to that of paclitaxel-carboplatin while reducing neurotoxicity and improving quality of life. We investigated the recommended doses of docetaxel-carboplatin in Japanese patients with ovarian cancer and conducted a comparative study of docetaxel-carboplatin versus paclitaxel-carboplatin. Methods Thirty-nine patients with ovarian cancer were enrolled in this study and 38 patients were evaluated. We conducted a dose-escalation study using a docetaxel dose of 70 mg/m² and carboplatin AUC 5 and 6. In the comparative study, patients received either docetaxel 70 mg/m² and carboplatin AUC 5 or paclitaxel 175 mg/m² and carboplatin AUC 5. Progression-free survival, survival rate at 2 years, response rate, toxicity, and quality of life were investigated. Results In the dose-finding study, we determined the recommended doses as docetaxel 70 mg/m² and carboplatin AUC 5. In the comparative study, the two arms showed similar progression-free survival. Grade 4 neutropenia occurred more frequently in the docetaxel-carboplatin group (84.6%) than in the paclitaxel-carboplatin group (43.8%), while sensory neurotoxicity was less frequent in the docetaxel-carboplatin group (53.8%) than in the paclitaxel-carboplatin (68.8%) group. There were significant differences in the quality-of-life data in favor of docetaxel-carboplatin. Conclusion We determined the recommended doses of docetaxel-carboplatin for Japanese patients with ovarian cancer to be docetaxel 70 mg/m² and carboplatin AUC 5. In the comparative study, we suggest that the docetaxel-carboplatin combination is effective and well tolerated as first-line chemotherapy for Japanese patients with ovarian cancer.     

A phase I study of estramustine, weekly docetaxel, and carboplatin chemotherapy in patients with hormone-refractory prostate cancer.

PURPOSE: To define the maximal tolerated dose, safety, and efficacy of docetaxel, carboplatin, and estramustine in patients with hormone-refractory prostate cancer (HRPC). METHODS: Patients with HRPC received docetaxel for 3 weeks, followed by a rest week. Docetaxel (20, 25, 30, 36, or 43 mg/m2) was given on days 2, 9, and 16 of a 28-day cycle. Patients also received estramustine (140 mg p.o. three times daily on days 1-5, 8-12, and 15-19) and carboplatin [area under the curve, AUC (5) or (6) on day 2]. RESULTS: Thirty patients were treated. Five patients received carboplatin [AUC (6)] but experienced delayed thrombocytopenia. After a protocol amendment, 25 subsequent patients received carboplatin [AUC (5)]. Median age was 64 years. Median prostate-specific antigen (PSA) was 117 ng/mL. Fifty-three percent received prior ketoconazole and 10% had mitoxantrone. No dose-limiting toxicities were noted. Although maximal tolerated dose was not reached, docetaxel dose escalation was stopped at 43 mg/m2. Significant myelosuppression was not seen until the highest dose level, when seven and four patients experienced grade 3 and 4 toxicities, respectively. Among all patients, PSA declines of > or =50% occurred in 63%. At the recommended phase II dose, PSA declines of > or =50% occurred in 75% (95% confidence interval, 43-95). Four of 14 (29%) patients with measurable disease had partial responses. Median survival was 14.6 months. CONCLUSIONS: Estramustine, docetaxel, and carboplatin are well tolerated and active in HRPC. Myelosuppression is the primary toxicity. The recommended phase II dose of docetaxel is 43 mg/m2 combined with estramustine and carboplatin. PSA declines were seen at every dose level.     

A phase I trial of oxaliplatin in combination with docetaxel in patients with advanced solid tumors

The primary objective of this trial was to establish the maximum tolerated dose (MTD) of oxaliplatin 130 mg/m² preceded by escalating doses of docetaxel 60 mg/m² (75, 90, 100 mg/m²) administered every 3 weeks. A total of 11 patients were entered; 10 evaluable for response: 4 stable disease (liver, ovary and esophagus) and 1 partial remission (esophagus). At dose level 1, there was 1 dose-limiting toxicity (DLT) (grade 3 allergic reaction). At dose level 2, there were 3 DLTs (3 grade 4 neutropenia, grade 3 gastritis, diarrhea, hypophosphatemia, neuro-mood). The MTD is docetaxel 60 mg/m² with oxaliplatin 130 mg/m².     

Pharmacokinetics,dynamics and toxicity of docetaxel: Why the Japanese dose differs from the Western dose

Docetaxel (Taxotere^®) has been one of the most important chemotherapeutic drugs for cancer treatment since 1996. Although a large number of clinical studies have been conducted in various cancer fields, there is a discrepancy in the standard dose between Japan and Western countries. This article reviews the pharmacokinetic, pharmacodynamic and toxicological profiles of docetaxel, and explains why there exists an ethnic difference in dose, and further discusses which direction we should go forward to solve this problem. The original recommended dose was 100 mg/m² every 3 weeks in US and European populations, while a Japanese phase I study suggested the recommended dose as 60 mg/m² every 3 weeks. A prospective population pharmacokinetic analysis of docetaxel conducted in both the USA/Europe and Japan, indicated an absence of ethnic difference in the pharmacokinetics. Both analyses demonstrated that docetaxel clearance is related to α1‐acid glycoprotein level, hepatic function, age and body surface area. The relationship was observed between increasing docetaxel dose and increased tumor response rates across the dose range of 60 to 100 mg/m². The area under the serum concentration time curve (AUC) of docetaxel at the first cycle was significantly related to time to progression. Hematological toxicities were well correlated with the AUC of docetaxel, and severe hematological toxicities were more frequently observed in Japanese patients treated with 60 mg/m², compared to the US/European patients treated with 75–100 mg/m² dose. The Japanese population seems more susceptible to the toxicity of docetaxel. A docetaxel dose of 75 mg/m² is now standard not only in global trials but also in recent Japanese trials. Although the optimal dose of docetaxel is still unclear, we need to continue to seek the appropriate dose of docetaxel depending on patient status and the goals of chemotherapy.     

Carcinoma of unknown primary site: Phase II trials with docetaxel plus cisplatin or carboplatin

Purpose:To evaluate the toxicity, response rate and short-termsurvival associated with the chemotherapy combinations of docetaxel pluscisplatin or carboplatin when used for the treatment of patients withmetastatic carcinoma of unknown primary site. Patients and methods:Twenty-six patients were treated withdocetaxel 75 mg/m² i.v. and cisplatin 75 mg/m² i.v.given every three weeks (study A) and subsequently, 47 patients were treatedwith docetaxel 65 mg/m² and carboplatin (AUC dose = 6) every threeweeks (study B). Stable or responding patients received a maximum of eightcourses of therapy. Patients who were known to be in treatable subset groupswere excluded from these trials. The majority of patients had two or moresites of metastasis; about 45% had adenocarcinoma and 50% poorlydifferentiated carcinoma. Results:In study A, 6 of 23 (26%) assessable patients hada major response to therapy. The median survival was eight months and one-yearsurvival 42%. Seven patients were removed from the study early forgrade 3 or 4 nausea and vomiting. In study B, 9 of 40 assessable patients(22%) had a major response to therapy. Median survival was eight monthsand one-year survival 29%. Toxicity associated with this regimen waspredominantly myelosuppression. Comparisons of the two sequential trialsshowed no differences in response rates or survivals (P = 0.75). Conclusions:Docetaxel and cisplatin (study A) is an activecombination in carcinoma of unknown primary site, but associated withsubstantial gastrointestinal toxicity. A combination of docetaxel pluscarboplatin (study B) is better tolerated and produced a similar responserate, median survival and one-year survival. Comparative phase III trials willbe necessary to unequivically prove a survival advantage for any form oftherapy in these patients. However, the survival for patients with carcinomaof unknown primary site receiving docetaxel-based chemotherapy is comparableto the survivals for several other groups of advanced cancer patients, suchas non-small cell lung cancer, receiving various types of chemotherapy.     

Results from a single institution phase II trial of concurrent docetaxel/carboplatin/radiotherapy followed by surgical resection and consolidation docetaxel/carboplatin in stage III non-small-cell lung cancer

Background

The optimal treatment of locally advanced non–small-cell lung cancer (NSCLC) remains controversial. We hypothesized that using a trimodality approach in selected patients with stage IIIA/IIIB disease would be both feasible and efficacious with reasonable toxicity.

Patients/Methods

We enrolled 13 patients with resectable stage III NSCLC on a prospective phase II trial of trimodality therapy. Induction treatment consisted of weekly docetaxel 20 mg/m² and weekly carboplatin at an area under curve (AUC) of 2 concurrent with 45 Gy thoracic radiotherapy. Resection was performed unless felt to be unsafe or if patients had progressive disease. Postoperative consolidation consisted of docetaxel 75 mg/m² and carboplatin at an AUC of 6 every 3 weeks for 3 cycles with growth factor support.

Results

All patients responded to induction chemoradiotherapy as measured by total gross tumor volume reductions of 43% on average (range, 27%-64%). Twelve patients underwent resection of the tumor and involved nodes, yielding a resectability rate of 92%. The primary endpoint of 2-year overall survival (OS) was 72% (95% confidence interval [CI], 36%-90%), and 2-year progression-free survival (PFS) was 36% (95% CI, 9%-64%). The maximal toxicity observed per patient was grade II in 5 patients (38%); grade III in 7 patients (54%); grade IV in 1 patient (8%); and grade V in none.

Conclusion

This trimodality approach resulted in promising outcomes with reasonable toxicity in carefully selected patients with stage III NSCLC at a single institution.     

Phase 1 and pharmacokinetic study of everolimus,a mammalian target of rapamycin inhibitor,in combination with docetaxel for recurrent/refractory nonsmall cell lung cancer

BACKGROUND:

Everolimus is a novel inhibitor of the mammalian target of rapamycin pathway, which is aberrantly activated in nonsmall cell lung cancer (NSCLC). The authors conducted a phase 1 and pharmacokinetic study of everolimus and docetaxel for recurrent NSCLC.

METHODS:

Patients with advanced stage NSCLC and progression after prior platinum‐based chemotherapy were eligible. Sequential cohorts were treated with escalating doses of docetaxel (Day 1) and everolimus (orally daily, Days 1‐19) every 3 weeks. Pharmacokinetic sampling of everolimus and docetaxel was done in Cycle 1. The primary endpoint was determination of the recommended phase 2 doses of the combination.

RESULTS:

Twenty‐four patients were enrolled (median age, 62 years; women, 11; number of prior regimens, 1 [n = 13], 2 [n = 6], ≥3 [n = 5]; Eastern Cooperative Oncology Group performance status, 0 [n = 6], 1 [n = 17]). The dose‐limiting toxicities (DLTs) were fever with grade 3/4 neutropenia, grade 3 fatigue, and grade 3 mucositis. None of the 7 patients treated at the recommended phase 2 dose (docetaxel 60 mg/m² and everolimus 5 mg daily) experienced DLT. Everolimus area under the concentration time curve (AUC) was not different with 60 or 75 mg/m² docetaxel. Mean ± standard deviation AUC‐based accumulation factors for everolimus on Days 8 and 15 were 1.16 ± 0.37 and 1.42 ± 0.42, respectively. Docetaxel Day 1 half‐life was 9.4 ± 3.4 hours. Among 21 patients evaluable, 1 had a partial response, and 10 had disease stabilization.

CONCLUSIONS:

The recommended phase 2 doses of docetaxel and everolimus for combination therapy are 60 mg/m² and 5 mg orally daily, respectively. Promising anticancer activity has been noted. Cancer 2010. © 2010 American Cancer Society.     

Dose escalation study of docetaxel and nedaplatin in patients with relapsed or refractory squamous cell carcinoma of the esophagus pretreated using cisplatin, 5-fluorouracil, and radiation

Background Definitive chemoradiation with cisplatin (CDDP) and 5-fluorouracil (5FU) has been playing an important role in the treatment of esophageal cancer, but some patients are not curable or have recurrent lesions. However, few chemotherapeutic regimens are available for such patients. Docetaxel and nedaplatin are active for esophageal cancer. We conducted a dose-escalation study of docetaxel and nedaplatin as second line-chemotherapy after definitive chemoradiation in patients with relapsed or refractory squamous cell carcinoma of the esophagus after chemoradiation. Methods Nedaplatin was administered on day 1 and docetaxel was administered on days 1 and 15, every 4 weeks. Dose escalation was based on the dose-limiting toxicity (DLT) observed during the first cycle. Results Twelve patients were enrolled. At a docetaxel dose of 30 mg/m² and a nedaplatin dose of 80 mg/m², one grade 4 neutropenia occurred and caused one treatment break longer than 2 weeks, but there were few DLTs. At doses of 35 and 80 mg/m², respectively, two grade 4 neutropenias and one grade 2 thrombopenia occurred and caused three treatment breaks longer than 2 weeks. Therefore, the maximum tolerated dose was established at this dose level. Two grade 3 anorexias and one grade 3 nausea occurred, but other non-hematological toxicities were generally mild. Responses were seen in one-fourth of the 12 patients, including one complete remission. Conclusion The recommended doses of docetaxel and nedaplatin were 30 and 80 mg/m², respectively. This combination could be a potential second-line treatment for this target population.     

A dose escalation study of weekly docetaxel in patients with advanced solid tumors

Purpose: To determine the maximum tolerated dose (MTD) and the dose-limiting toxicity (DLT) of weekly administration of docetaxel for three consecutive weeks every 4 weeks in patients with advanced solid tumors. Patients and methods: A total of 26 patients with malignant tumors refractory to conventional treatment were enrolled in this phase I study; their median age was 62 years. Of the 26 patients, 16 (62%) had previously received more than one chemotherapy regimen and 17 (65%) had previously received taxanes in a 3-week schedule. Docetaxel was administered after appropriate premedication at escalating doses (starting dose 30 mg/m²) as a 1-h i.v. infusion for three consecutive weeks in cycles of 4 weeks. Results: A total of 68 chemotherapy cycles were administered with a median of three cycles per patient (range one to six). The DLT was reached at 45 mg/m² per week and the dose-limiting events were grade 4 neutropenia, febrile neutropenia, and treatment delay due to incomplete hematologic recovery. The MTD was defined at a dose of 42 mg/m²/week. Grade 3/4 neutropenia occurred in seven patients (27%) (10% of cycles), and four patients (15%) developed febrile neutropenia. There were no deaths due to sepsis. Grade 2 peripheral neurotoxicity was observed in two patients (8%), grade 2 and 3 fatigue in 14 (54%), grade 2 edema in seven (27%), mild allergic reactions in two (8%) and lacrimation in three (12%). One (4%) complete response and eight (35%) partial responses (overall response rate 39%) were observed in 23 evaluable patients. Stable disease and progressive disease were observed in six patients (26%) and eight patients (35%), respectively. All responses were observed in patients with metastatic breast cancer, one of whom had progressed on paclitaxel-based and two of whom had progressed on docetaxel-based chemotherapy. Conclusions: The weekly administration of docetaxel for three consecutive weeks every 28 days is a feasible schedule with a favorable toxicity profile, and can be given on an outpatient basis. Moreover, this schedule of docetaxel administration seems to have an enhanced efficacy, especially in patients with advanced breast cancer who have failed front-line taxane-based chemotherapy. Received: 27 February 2000 / Accepted: 28 July 2000     

Phase II trial of neoadjuvant chemotherapy with docetaxel,nedaplatin, and S1 for advanced esophageal squamous cell carcinoma

Although standard chemotherapy for esophageal cancer patients is fluorouracil and cisplatin, the prognosis is still unsatisfactory. A new therapeutic regimen combining docetaxel, cisplatin, and 5‐fluorouracil was recently developed to improve both local and distant tumor control. We developed a new regimen of docetaxel, nedaplatin, and S1 (DGS) and previously reported the recommended dose in a phase I dose‐escalation study. We then undertook a phase II study of DGS for advanced esophageal squamous cell carcinoma. Patients with clinical stage IB/II/III disease were eligible. Patients received two courses of chemotherapy: docetaxel 35 mg/m² with nedaplatin 40 mg/m² on day 8, 80 mg/m² S1 on days 1–14, and 2 weeks off. After completion of chemotherapy, patients underwent esophagectomy. The primary endpoint was the completion rate of protocol treatment (completion of two courses of preoperative chemotherapy and R0 surgery [no residual tumor]). We enrolled 32 patients. The completion rate of protocol treatment was 96.9%. During chemotherapy, the most common grade 3 or 4 toxicity was neutropenia (25.0%). No treatment‐related deaths were observed, and the incidence of operative morbidity was tolerable. The overall response rate after chemotherapy was 83.3%. This DGS regimen was well tolerated and highly active. This trial is registered with the University Hospital Medical Information Network (UMIN ID: 000014626).     

Phase I trial of weekly docetaxel with a 4-weekly cisplatin administration in patients with advanced gastric carcinoma

The docetaxel-cisplatin combination is active against several tumors including gastric cancer but it is followed by severe myelosuppression. Recent experience with weekly taxanes has demonstrated a mild myelotoxicity with high dose intensity. We investigated in a phase I study a weekly schedule of docetaxel on days 1, 8 and 15 and cisplatin on day 1 every 4 weeks in 19 patients with advanced gastric cancer with no prior chemotherapy. Cohorts of patients were treated with escalating doses of docetaxel (starting dose 30 mg/m² per week and increments of 10 mg/m² per week) and cisplatin (starting dose 70 mg/m² and increments of 5 mg/m²). Febrile neutropenia was the only dose-limiting event occurring in four (20%) patients; the dose-limiting toxicity was reached at dose level three (docetaxel 40 mg/m² per week and cisplatin 75 mg/m²). The maximum-tolerated dose was 40 mg/m² per week for docetaxel and 70 mg/m² every 4 weeks for cisplatin. Grade 3/4 neutropenia occurred in six patients (30%); early death occurred in one patient with septic shock because of neutropenia and another with acute coronary ischemia. Two (11%) complete and two (11%) partial responses were documented (ORR 22%; 95% CI 3–39%), with a median response duration of 5 months and median time to progression of 7 months. In conclusion, the combination of weekly docetaxel plus cisplatin is feasible with moderate toxicity and merits further investigation in phase II studies in advanced gastric cancer.Presented as an abstract at the 15th International Congress on Anti-Cancer Treatment, Paris, 9–12 February 2004.     

Carboplatin with weekly docetaxel and ifosfamide in advanced head and neck cancers: a phase I Brown University Oncology Group dose escalation study (HN-93)

Purpose

A phase I study was performed to determine the maximally tolerated dose of carboplatin, ifosfamide, and docetaxel in advanced head and neck cancers.

Methods

Carboplatin (week 1) was administered with weekly docetaxel and ifosfamide for 3 weeks in an every 4-week cycle. Restaging was done after two cycles, while dose level escalation was done in cohorts of three patients.

Results

Fifteen patients (recurrent/metastatic disease, n = 8; bulky locally advanced disease, n = 7) were enrolled. No dose-limiting toxicities were observed. Toxicities included grade 3 neutropenia and anemia (n = 2, each), and grade 2 thrombocytopenia (n = 3). The final level of carboplatin AUC = 6 (week 1) with docetaxel 30 mg/m² per week and ifosfamide 1,000 mg/m² per week was chosen for further evaluation.

Conclusions

This novel regimen of carboplatin with weekly docetaxel and ifosfamide has a favorable toxicity profile and is active in this setting. Phase II study results are awaited.     

Protective effect of amifostine against toxicity of paclitaxel and carboplatin in non-small cell lung cancer

Aim: In this study we determined the protective role of amifostine against the side effects of the combination of paclitaxel and carboplatin in patients with non-small cell lung cancer (NSCLC). Patients and Methods: Chemo-naive patients with NSCLC were eligible. Thirty-eight patients were randomized to receive paclitaxel 175 mg/m² and carboplatin AUC=6 with amifostine 910 mg/m² (group B) or chemotherapy alone (group A). The occurrences of hematologic, neurologic, cardiologic toxicities, and ototoxicity were evaluated. Results: All patients completed the six scheduled cycles of therapy. A total of 114 cycles of chemotherapy was given in both groups. Neutropenia grade 3–4 was observed in 11 cycles (9.6%) in group A and 19 cycles (16.6%) in group B (p=0.16). Paresthesia grade 1 or 2 was observed in 18 of 19 patients of group A and in 8 of 19 patients of group B, following the sixth cycle of chemotherapy (p=0.018). Two patients of group B and nine patients of group A suffered from sensory motor impairment grade 2 (p=0.029). There was no clinical evidence in any patient for deterioration in cardiac function. Asymptomatic and transient sinus bradycardia or ventricular premature beats developed in four patients. None of the patients reported vertigo, tinnitus, or hearing loss. Conclusion: The addition of the amifostine to the combination of paclitaxel and carboplatin may prevent or reduce the incidence of neurotoxicity in the treatment of NSCLC. Amifostine does not appear to have a preventive role in neutropenia.     

Cetuximab in combination with carboplatin and docetaxel for patients with metastatic or advanced-stage nonsmall cell lung cancer: a multicenter phase 2 study

BACKGROUND.

Cetuximab, an immunoglobulin (Ig) G1 chimeric monoclonal antibody against the epidermal growth factor receptor, has demonstrated evidence of activity in nonsmall cell lung cancer (NSCLC). When administered in combination with carboplatin and docetaxel, a commonly used regimen for advanced NSCLC, cetuximab has exhibited synergistic interaction in preclinical studies. Therefore, a phase 2 study was conducted to evaluate the efficacy of the combination of cetuximab, carboplatin, and docetaxel for the treatment of advanced NSCLC.

METHODS.

Chemotherapy‐naïve patients aged ≥18 years with stage IIIB (with effusion) or stage IV NSCLC received cetuximab (at a dose of 400 mg/m² on Day 1 and 250 mg/m² on Days 8 and 15) plus docetaxel (at a dose of 75 mg/m² on Day 1) and carboplatin (area under the concentration vs time curve [AUC] = 6 on Day 1) every 21 days for up to 6 cycles (graded according to the American Joint Committee on Cancer Staging System). Thereafter, patients without evidence of disease progression were continued on single‐agent cetuximab for a maximum of 1 year or until disease progression. The primary endpoint was response rate.

RESULTS.

Eighty patients were enrolled. The median number of cycles administered was 4 (range, 1‐6 cycles). The objective response rate was 15.2%, with a median progression‐free survival of 4.6 months and a median overall survival of 10.3 months. The salient grades 3 of 4 adverse events were neutropenia (30%), hypotension (3%), hypokalemia (4%), and hypomagnesemia (3%). Twenty‐five patients received single‐agent cetuximab (median duration, 12 weeks) and this was well tolerated.

CONCLUSIONS.

The results of this large, multicenter, phase 3 study indicate that the novel combination of cetuximab with docetaxel and carboplatin demonstrate modest anticancer activity for patients with advanced and metastatic NSCLC and has an acceptable toxicity profile. Cancer 2008. © 2008 American Cancer Society.