Phase I study of 3-weekly docetaxel, capecitabine and oxaliplatin combination chemotherapy in patients with previously untreated advanced gastric cancer

Purpose

Adding docetaxel to cisplatin and 5-fluorouracil (5-FU) (DCF) significantly improved clinical efficacy in advanced gastric cancer (AGC). To further improve the efficacy and tolerability, we substituted oxaliplatin for cisplatin and capecitabine for 5-FU in the DCF regimen and performed a phase I study to determine the recommended dose (RD) and dose-limiting toxicity (DLT) of docetaxel, capecitabine and oxaliplatin (DXO) combination in patients with AGC.

Materials and methods

Previously untreated patients with histologically proven metastatic AGC and ECOG performance status 0–2 were enrolled. Docetaxel and oxaliplatin were administered i.v. on day 1. Capecitabine was administered orally bid on days 1–14. Each cycle was repeated every 3 weeks. DLTs were evaluated during the first two cycles of treatment.

Results

Twenty-one patients were enrolled: 15 patients in dose-escalation phase and 6 patients in the extension at the RD. Median age was 50 years (range 21–65 years). At dose level 3 (60 mg/m² docetaxel, 1,000 mg/m² capecitabine, 100 mg/m² oxaliplatin), 1 diarrhea (DLT) was found among 6 patients while at dose level 4 (60 mg/m² docetaxel, 800 mg/m² capecitabine, 130 mg/m² oxaliplatin), 2 DLTs (febrile neutropenia and diarrhea) were observed among 3 patients. Therefore, the dose level 3 was determined as RD. DLTs include grade 3 diarrhea and febrile neutropenia. Cumulative (all cycles) grade 3/4 toxicity included neutropenia (75%), leucopenia (50%), febrile neutropenia (25%), diarrhea (17%), and neuropathy (17%). Of 14 patients with measurable lesions, 11 achieved partial response and 3 showed stable disease.

Conclusion

The RD of the DXO regimen in patients with AGC is capecitabine 1,000 mg/m² twice daily on days 1–14, in combination with decetaxel 60 mg/m² (day 1) and oxaliplatin 100 mg/m² (day 1) repeated every 3 weeks. The DXO regimen seems to have promising activity and offers an easy alternative to DCF. The toxicities appear to be still substantial, but manageable.     

Biweekly docetaxel,fluorouracil, leucovorin,oxaliplatin (TEF) as first-line treatment for advanced gastric cancer and adenocarcinoma of the gastroesophageal junction: safety and efficacy in a multicenter cohort

Background

Docetaxel–cisplatin-5-FU chemotherapy is superior to 5-FU-cisplatin in terms of response rate and survival in advanced gastric cancer (AGC), but is more toxic. Oxaliplatin is better tolerated than cisplatin, which it can effectively replace in this setting. We hypothesize that incorporating docetaxel into a simplified FOLFOX regimen should be a tolerable and effective option in first-line treatment of AGC.

Methods

Data were collected at six  French centers from patients with metastatic or local AGC who received docetaxel, fluorouracil, leucovorin, or oxaliplatin (TEF) as first-line treatment. TEF was administered as follows: docetaxel (50 mg/m²), oxaliplatin (85 mg/m²), and leucovorin (40 mg/m²) on day 1, and 5-FU continuous infusion for 48 h (2400 mg/m²) every 2 weeks.

Results

Forty-one patients were enrolled. Performance status was grade 0 and 1 in respectively 27 and 58 % of patients; 17 patients had adenocarcinoma of the gastroesophageal junction; 37 patients had metastatic disease, 22 had a poorly differentiated or diffuse type. Objective response rate was 66 %, with a complete response in two patients (5 %). Median progression-free survival and overall survival were respectively 6.3 and 12.1 months. Tolerability was acceptable with no treatment-related deaths. The most frequent grade 3–4 toxicities were neutropenia (30 %) and neuropathy (12.5 %). Curative intent surgery after response to TEF was performed in seven patients (17 %).

Conclusion

TEF is an effective first-line treatment with an acceptable toxicity profile for patients with AGC. It may allow curative resection in initially unresectable patients. TEF should now be evaluated in prospective randomized trials.     

Feasibility and toxicity of docetaxel before or after fluorouracil, epirubicin and cyclophosphamide as adjuvant chemotherapy for early breast cancer

Background

The tolerance and safety associated with the administration order of the anthracycline and taxane drugs have not been evaluated.

Patients and methods

Breast cancer patients with node-positive or high-risk patients with node-negative were eligible. The feasibility and toxicity were evaluated in the following regimens—arm A, 3 courses of fluorouracil 500 mg/m², epirubicin 100 mg/m² and cyclophosphamide 500 mg/m² (FEC) followed by 3 courses of docetaxel 100 mg/m² (DOC); arm B, 3 courses of DOC followed by 3 courses of FEC.

Results

Forty-two patients were registered. The relative dose intensity was 94.2 % for FEC and 97.8 % for DOC in arm A, and 98.9 % for DOC and 95.2 % for FEC in arm B. In arm A, grade 3 or higher hematological toxicity was observed in nine patients, and febrile neutropenia developed in three patients with FEC. In arm B, grade 3 or higher hematological toxicity was observed in seven patients, but febrile neutropenia was not noted in any patient.

Conclusion

The regimens in both arms A and B were safe regarding adjuvant chemotherapy for early breast cancer. However, DOC followed by FEC might be more tolerable. Further studies will maximize the results obtained with DOC followed by FEC.     

The Breast Avastin Trial: phase II study of bevacizumab maintenance therapy after induction chemotherapy with docetaxel and capecitabine for the first-line treatment of patients with locally recurrent or metastatic breast cancer

Background

Therapeutic approach for patients with metastatic breast cancer (MBC) is still controversial. This study was conducted to assess the efficacy and safety of bevacizumab in combination with docetaxel plus capecitabine as first-line treatment for MBC. The feasibility of bevacizumab maintenance therapy in this setting was also evaluated.

Patients and methods

In this single-arm, multicenter phase II study, patients received bevacizumab 15 mg/kg and docetaxel 60 mg/m² on day 1, plus capecitabine 900 mg/m² twice daily on days 1–14 every 21 days. Treatment was administered for up to 6 cycles, then bevacizumab continued until progressive disease. The primary end point was progression-free survival (PFS); secondary end points were tumor response rate, overall survival, and toxicity.

Results

Seventy-nine eligible patients were treated with bevacizumab in combination with docetaxel plus capecitabine. The overall response rate was 61 %, with a complete response rate of 8 % and a median duration of response of 10 months. At a median follow-up of 28 months, the median PFS was 11 months. Fifty-two (65 %) patients received bevacizumab maintenance therapy for a median duration of 7 months (range 1 to 33+). Neutropenia was the most common grade 3–4 toxicity (28.1 % of patients), and two fatal adverse events occurred (septic shock and gastrointestinal perforation).

Conclusions

Bevacizumab in combination with docetaxel and capecitabine demonstrates significant activity and quite acceptable toxicity profile as first-line treatment of MBC. Subsequent maintenance therapy with bevacizumab is feasible for a long period of stable disease. Results deserve confirmation.     

A Phase II Study of Capecitabine, Oxaliplatin, and Cetuximab with or Without Bevacizumab as Frontline Therapy for Metastatic Colorectal Cancer. A Fox Chase Extramural Research Study

Objectives

Dual inhibition of vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) demonstrated initial promise in clinical trials. This phase II study tested the efficacy and safety of capecitabine, oxaliplatin, and cetuximab with or without bevacizumab as first-line treatment for metastatic colorectal cancer patients.

Methods

Patients were randomized to receive capecitabine 850 mg/m² PO twice daily for 14 days, oxaliplatin 130 mg/m² IV day 1, and cetuximab 400 mg/m² IV loading dose followed by 250 mg/m² IV days 1, 8, and 15 with (Arm A) or without (Arm B) bevacizumab 7.5 mg/kg IV day 1 every 21 days. Tumor samples were collected and retrospectively analyzed for KRAS mutation status. The primary endpoint was response rate, with time to progression (TTP) and overall survival (OS) as secondary objectives.

Results

Twenty-three patients (12 in Arm A, 11 in Arm B) were enrolled onto the study. Median follow-up was 25.9 months. Both treatments were well tolerated, with expected higher rates of grade 1/2 hypertension and bleeding in Arm A. The overall response rate was 54% (36.4% in Arm A and 72.7% in Arm B). Median time to progression was 8.7 months in Arm A and 14.4 months in Arm B. The median survival was 18.0 months in Arm A and 42.5 months in Arm B. The study was prematurely terminated after other studies reported inferior outcomes with dual antibody therapy.

Conclusions

Although terminated early, the study supports the detrimental effect of combining VEGF and EGFR inhibition in metastatic colorectal cancer.     

A phase II study of oxaliplatin in combination with leucovorin and fluorouracil as first-line chemotherapy in patients with metastatic squamous cell carcinoma of esophagus

Purpose

Squamous cell carcinoma is the main histological subtype of esophageal cancer in the east Asia. Oxaliplatin and fluorouracil are active agents for esophageal carcinoma. The aim of this phase II study was to evaluate the efficacy and safety of oxaliplatin, fluorouracil and leucovorin in patients with metastatic esophageal squamous cell carcinoma (ESCC).

Methods

Patients with metastatic ESCC and Eastern Cooperative Oncology Group performance score of 0–2 who had not received prior systemic chemotherapy for metastatic disease were enrolled. Oxaliplatin, 100 mg/m², was administered as a 2-h intravenous (i.v.) infusion on day 1. Leucovorin, 400 mg/m² i.v., was administered as a 2-h infusion followed by fluorouracil (400 mg/m²) i.v. bolus immediately followed by fluorouracil (2,400 mg/m²) as a 46-h continuous infusion on days 1 and 2. Chemotherapy was repeated every 14 days.

Results

Between October 2008 and September 2011, fifty-six patients, with a median age of 59 years, were enrolled in this study. The overall response rate was 23.2 % with a disease control rate of 67.9 %. The median progression-free survival (PFS) was 4.4 months, and the median overall survival (OS) was 7.7 months. Median PFS was significantly longer in patients without liver metastasis than those with liver metastasis (5.4 vs 2.4 months, P = 0.003). Partial response was associated with longer PFS (7.2 vs 2.7 months, P = 0.023) and OS (11.3 vs 7.1 months, P = 0.028). Significant difference in OS was noted between those age >65 and ≤65 years of age (7.9 vs 3.3 months, P = 0.033). Grade 3/4 neutropenia, leucopenia, anemia and thrombocytopenia occurred in 35.7, 28.6, 10.7 and 10.7 % of patients, respectively. The most common non-hematologic toxicities were fatigue, mucositis, nausea/vomiting and peripheral neuropathy, all of which were moderate, reversible and did not require a dose reduction.

Conclusions

Chemotherapy with oxaliplatin, leucovorin and fluorouracil showed moderate antitumor activity in metastatic ESCC and was well tolerated with acceptable myelosuppression, infrequent and reversible non-hematologic toxicities in patients with ESCC.     

Sequential administration of dose-dense epirubicin/cyclophosphamide followed by docetaxel/capecitabine for patients with HER2-negative and locally advanced or node-positive breast cancer

Purpose

Capecitabine is effective against metastatic breast cancer (MBC). We hypothesized that sequential treatment with dose-dense epirubicin/cyclophosphamide (EC) and docetaxel/capecitabine would be active and tolerable in the adjuvant/neoadjuvant setting.

Methods

In this prospective phase II clinical trial patients with HER2-negative and node-positive or locally advanced tumors were eligible to receive four cycles of EC (100/600 mg/m²) every 2 weeks with G-CSF on days 3–10, followed by four cycles of docetaxel/capecitabine (75/1,000 mg/m² b.i.d., days 1–14) every 3 weeks.

Results

Fifty-five patients were enrolled with median age of 49, and 80% had hormone receptor-positive disease. The median tumor size was 2.5 cm, with a median of two axillary nodes involved. Seventy-five percent of the first 20 patients had grade 2/3 hand-foot syndrome (HFS). Dose reduction of capecitabine to 800 mg/m² reduced the grade 2/3 HFS incidence to 31% in the remaining patients. No grade 4/5 toxicities were observed. All 20 patients treated preoperatively responded, with 5 (25%) pathologic complete responses and 3 additional pT₀N₁ tumors. At a median follow-up of 48 (range 28–60) months, the event-free and overall survival rates are 91 and 98%, respectively.

Conclusions

Sequential treatment with dose-dense EC followed by docetaxel/capecitabine, using a lower capecitabine dose than that approved for MBC, has an acceptable toxicity profile and encouraging activity when used as neoadjuvant or adjuvant treatment of breast cancer.     

A phase II study of oxaliplatin, docetaxel, and GM-CSF in patients with previously treated advanced melanoma

Purpose

Although much focus has been placed on immunotherapy for melanoma, further development of chemotherapy approaches is needed. Melanoma is responsive to platinum compounds and taxanes, but there is limited experience with combinations of these agents. Oxaliplatin has been reported to have detectable activity in melanoma, and a phase I study has identified a tolerable dose and schedule of oxaliplatin in combination with docetaxel and hematopoietic growth factor support. GM-CSF has a theoretical advantage of immune potentiation. These considerations supported the study of oxaliplatin, docetaxel, and GM-CSF in patients with advanced melanoma.

Methods

Eligibility included adequate organ function, PS ≤ 2, at most one prior chemotherapy and one prior immunotherapy, no prior treatment with oxaliplatin or taxanes and no chremophor allergy. After premedication, docetaxel was administered day 1 at 75 mg/m², then oxaliplatin on day 2 at 85 mg/m². GM-CSF (250 mcg/m²) was administered s.c. days 3–12. Cycles were 21 days in length, and disease reevaluation was performed every two cycles by RECIST criteria.

Results

Nineteen patients received at least one cycle, eight with one prior systemic therapy, five with two prior systemic therapies. Five patients did not complete two cycles and were not formally evaluable for response. Five patients had stable disease (SD), including one who failed two prior therapies and went on to receive ten cycles. The remaining nine patients displayed progressive disease (PD) after two cycles. Notable toxicities included seven cases (37%) of grade III/IV neutropenia and two (11%) hypersensitivity reactions.

Conclusions

This combination of oxaliplatin, docetaxel, and GM-CSF has limited clinical activity in previously treated patients with advanced melanoma. Exploration in treatment-naïve patients may still be warranted.     

Phase I trial of docetaxel, oxaliplatin, and capecitabine (DOC) in untreated gastric cancer patients

Background

A combination of docetaxel (D), oxaliplatin (O), and capecitabine (C) (DOC) was studied in this dose-escalation phase Ib trial in patients with untreated advanced gastric cancer.

Methods

Dose-limiting toxicity (DLT) included any grade 4 hematological or any grade 3 non-hematological toxicity, besides alopecia and nausea or vomiting. Cohorts of three patients, expanded to six if one DLT occurred, were studied. Two DLTs out of three patients, or ≥3 out of six patients defined the toxic level. The preceding level, maximum tolerated dose (MTD), was further expanded to nine patients. The primary objective was to establish the MTD of the DOC regimen.

Results

Twenty-one patients entered four dose levels. Levels I, II, and IIb were considered safe and included 3, 6, and 6 patients, respectively. Level III defined our toxic level with three analyzed patients. Therefore, level IIB was expanded to 9 patients. No other DLTs were recorded.

Conclusions

Fractionation of doses and the use of less toxic and more convenient derivatives are the rationales for this new combination. The MTD (mg/m²) was: D, 30 and O, 70, both on days 1 and 8, i.v.; C 1000 per day, days 2–15, p.o.; all given every 3 weeks. A cooperative phase II study has been opened.     

Experience with combination of docetaxel, cisplatin plus 5-fluorouracil chemotherapy, and intensity-modulated radiotherapy for locoregionally advanced nasopharyngeal carcinoma

Background

Our aim was to evaluate the efficacy and toxicity of cisplatin, fluorouracil, and docetaxel chemotherapy plus intensity-modulated radiotherapy (IMRT) for locoregionally advanced nasopharyngeal carcinoma (NPC).

Methods

Sixty patients with locoregionally advanced NPC were enrolled. Patients received IMRT plus three courses of neoadjuvant chemotherapy and two courses of adjuvant chemotherapy consisting of docetaxel (60 mg/m²/day on day 1), cisplatin (25 mg/m²/day on days 1–3), and 5-fluorouracil (500 mg/m²/day on days 1–3).

Results

The overall response rate to neoadjuvant chemotherapy was 89 %. Three months after the completion of radiotherapy, 53 (93 %) patients achieved complete regression, 3 (5 %) achieved partial response (PR), and 1 experienced liver metastasis. However, among the 3 PR patients, 2 patients had no evidence of relapse in the follow-up. With a median follow-up of 27 months (range, 6–43), the 2-year estimated locoregional failure-free survival, distant failure-free survival, progression-free survival, and overall survival were 96.6, 93.3, 89.9, and 98.3 %, respectively. Leukopenia was the main adverse effect in chemotherapy; 14 patients experienced grade 3 or grade 4 neutropenia, and 1 patient developed febrile neutropenia. The nonhematological adverse events included alopecia, nausea, vomiting, anorexia, and diarrhea. The incidence of grade 3 acute radiotherapy-related mucositis was 28.3 %; no grade 4 acute mucositis was observed. No grade 3 or grade 4 hematological toxicity occurred during radiotherapy. None of the patients had interrupted radiotherapy. The common late adverse effects included xerostomia and hearing impairment.

Conclusions

Neoadjuvant–adjuvant chemotherapy using cisplatin, fluorouracil, plus docetaxel combined with IMRT was an effective and well-tolerated alternative for advanced NPC.     

A phase II study of capecitabine plus docetaxel in gemcitabine-pretreated metastatic pancreatic cancer patients: CapTere

Purpose

Docetaxel and capecitabine combination is synergistic in preclinical models. We investigated the efficacy and toxicity of this combination as second-line chemotherapy in patients with metastatic pancreatic adenocarcinoma (mPC), pretreated with gemcitabine-based chemotherapy.

Methods

Eligible patients were treated with capecitabine 800 mg/m² orally PO bid on days 1–14 in combination with intravenous docetaxel 30 mg/m² on days 1 and 8 of each 21-day cycle. The primary end point was overall response rate. Using a three-stage sequential design, two interim analyses for early stopping due to lack of efficacy were planned and conducted after 13 and 26 patients were accrued. Secondary end points included time to treatment failure, progression-free survival (PFS), overall survival (OS) and 50 % drop in CA19-9 levels.

Results

Forty-three patients were evaluable for toxicity and 42 evaluable for response, at a median age of 64 years. The majority of patients (74 %) had ECOG PS 0-1. Six patients (14 %) achieved a partial tumor response, and stable disease for ≥2 cycles was observed in 59 % of patients (n = 25). Thirty-five percent (n = 11/31) of patients had a ≥50 % decrease in CA19-9 levels. The median PFS was 3.7 months (95 % CI 2.1–4.3 months), and the median OS was 5.3 months (95 % CI 4.3–8.6 months). Treatment was generally well tolerated. Grade 3 toxicity and grade 4 toxicity were seen in 45 and 5 % of patients, respectively. One patient had a potential treatment-related mortality.

Conclusions

The combination of capecitabine and docetaxel is active and well tolerated in mPC patients pretreated with gemcitabine-based therapy.     

Multicenter randomized phase II clinical trial of oxaliplatin reintroduction as a third- or later-line therapy for metastatic colorectal cancer—biweekly versus standard triweekly XELOX (The ORION Study)

Background

The aim of this multicenter, open-label, randomized phase II trial was to evaluate the efficacy of a dose-dense capecitabine and oxaliplatin (XELOX) regimen in patients with metastatic colorectal cancer (mCRC) for whom reintroduction of oxaliplatin had been planned as a third- or later-line regimen.

Methods

The patients with mCRC who had received prior chemotherapy including oxaliplatin and were scheduled for reintroduction of oxaliplatin were randomized to capecitabine (1,000 mg/m²) twice daily on days 1–14 and oxaliplatin (130 mg/m²) on day 1 every 21 days (Q3W group) or capecitabine (2,000 mg/m²) twice daily on days 1–7 and oxaliplatin (85 mg/m²) on day 1 every 14 days (Q2W group). The primary endpoint was the time-to-treatment failure (TTF). Other endpoints included overall survival (OS), progression-free survival (PFS) and other adverse events (AEs).

Results

A total of 46 patients were enrolled in the trial—22 patients were randomly assigned to the Q3W group and 23 to the Q2W group. The median TTF was 3.4 months in both groups (hazard ratio [HR] 1.053; p = 0.880). The median PFS and OS were 3.3 and 9.2 months in the Q2W group and 4.3 and 12.1 months in the Q3W group, respectively (HR 1.15; p = 0.153 and 0.672; p = 0.836). The most common grade 3?4 AEs in the Q3W and Q2W groups were fatigue (27.3 vs 21.7), neuropathy (9.1 vs 0 %) and diarrhea (9.1 vs 0 %), respectively.

Conclusion

There was no significant inter-group difference in any of the efficacy and safety endpoints, including TTF, OS, RFS and AEs. The results of this clinical trial were convincingly negative.

     

Salvage chemotherapy with docetaxel and pegylated liposomal doxorubicin in pretreated patients with platinum- and taxane-sensitive ovarian cancer: a multicenter phase II trial of the Hellenic Oncology Research Group (HORG)

Purpose

To evaluate the safety and antitumor activity of docetaxel (DOC) and pegylated liposomal doxorubicin (PLD) combination in patients with platinum- and taxane-sensitive ovarian cancer.

Patients and methods

Twenty-three patients were enrolled. DOC was administered at the dose of 40 mg/m² intravenously (i.v.) and PLD at 20 mg/m² i.v. on days 1 and 15 in cycles of 28 days. The study was closed prematurely due to slow accrual.

Results

Seven (30.4 %) patients achieved objective response (three complete, four partial), while five (21.7 %) others experienced stable disease (overall disease control rate 52.1 %). The median progression-free survival was 4.8 months and the median overall survival 18.8 months. Grade 3–4 neutropenia occurred in two (8.7 %) and one (4.3 %) patients, respectively. Febrile neutropenia occurred in two patients. The most common non-hematological grade 3 toxicity was hand-foot syndrome (13 % of patients). There was no treatment-related death.

Conclusions

The combination of pegylated liposomal doxorubicin and docetaxel is a well tolerated and a relatively active regimen in pretreated patients with platinum- and taxane-sensitive advanced ovarian cancer.     

A phase II study of neoadjuvant docetaxel, oxaliplatin, and S-1 (DOS) chemotherapy followed by surgery and adjuvant S-1 chemotherapy in potentially resectable gastric or gastroesophageal junction adenocarcinoma

Purpose

Adjuvant chemotherapy trial of TS-1 for gastric cancer study demonstrated that postoperative S-1 chemotherapy for 1 year improved overall survival of locally advanced gastric cancer (LAGC) patients. The goals of this study were to evaluate the feasibility and efficacy of neoadjuvant docetaxel, oxaliplatin, and S-1 (DOS) chemotherapy followed by surgery and adjuvant S-1 chemotherapy.

Methods

In this single-center, open-label, phase II study, patients with potentially resectable adenocarcinoma of the stomach or gastroesophageal junction were eligible. For neoadjuvant chemotherapy, docetaxel 50 mg/m² on day (D) 1, oxaliplatin 100 mg/m² on D1, and S-1 40 mg/m² bid orally on D1–14 were administrated every 3 weeks for three cycles. After DOS chemotherapy, gastrectomy was performed, and then, adjuvant S-1 40 mg/m² bid was given on D1–28 every 6 weeks for 1 year. The primary endpoints were the proportion of patients who did not experience grade 3 or 4 toxicities (except grade 3 neutropenia) and R0 resection rates.

Results

A total of 41 patients were enrolled. All patients completed three planned cycles of neoadjuvant chemotherapy without disease progression. Eighteen patients (43.9 %) did not experience any grade 3–4 toxicity (except grade 3 neutropenia) during the neoadjuvant chemotherapy. All patients underwent surgery, and R0 resection was achieved in 40 patients (97.6 %).

Conclusion

Neoadjuvant DOS chemotherapy could be performed safely with a high R0 resection rate in LAGC patients. A phase III trial is currently underway.     

Phase II study of S-1 and docetaxel for previously treated patients with locally advanced or metastatic non-small cell lung cancer

Purpose

The purpose of the present phase II study was to evaluate both the efficacy and toxicity of the combination of S-1 and docetaxel in previously treated patients with locally advanced or metastatic non-small cell lung cancer.

Methods

Thirty-eight previously treated patients with non-small cell lung cancer were treated with S-1 (80 mg/m², days 1–14, oral) and docetaxel (40 mg/m², day 1, intravenous) every 3 weeks.

Results

No complete response was observed, and seven patients had a partial response, yielding an overall response rate of 18.4% (95% CI, 7.7–34.3%). The median overall survival time and 1-year overall survival rate were 16.1 months and 60%, respectively. The median progression-free survival time was 4.4 months. Myelosuppression was the main toxicity with grade 3 or 4 neutropenia and leukopenia in 50 and 21%, respectively. There was no irreversible toxicity in this study.

Conclusions

The combination of S-1 and docetaxel is well tolerable and has substantial activity for patients with locally advanced or metastatic non-small cell lung cancer. A phase III trial comparing docetaxel with or without S-1 would warrant further investigation.     

Phase I Study of Oxaliplatin in Combination with Gemcitabine, Irinotecan, and 5-Fluorouracil/Leucovorin (G-FLIE) in Patients with Metastatic Solid Tumors Including Adenocarcinoma of the Pancreas

Purpose

The aims of this study were to establish the maximum tolerated dose (MTD) of oxaliplatin in combination with fixed doses of gemcitabine, irinotecan, and 5-fluorouracil/leucovorin (G-FLIE) in solid tumors, including advanced pancreatic cancer, and to evaluate the toxicity of the regimen.

Methods

Patients with metastatic solid tumors were treated with a regimen consisting of gemcitabine (500 mg/m² by fixed-dose-rate infusion), irinotecan (120 mg/m²), leucovorin 300 mg, bolus/infusion 5-fluorouracil (400 and 1,500 mg/m2, respectively), and oxaliplatin at doses from 50 to 85 mg/m² according to the escalation schema. Treatment was repeated every 14 days.

Results

The study enrolled 25 patients with a median age of 64 years and median Karnofsky performance score of 80. Patients had metastatic adenocarcinomas of pancreas (n?=?9), as well as gastroesointestinal, hepatobiliary, or unknown primary tumors. With only one dose limiting toxicity (neutropenia and constipation), the MTD of oxaliplatin was not reached up to the pre-specified maximum level of 85 mg/m². Other toxicities predictably included cytopenias, fatigue, sensory neuropathy, nausea/vomiting, diarrhea, and constipation. Four partial responses and ten disease stabilizations were observed. The overall median time to disease progression was 17 weeks (2–110 weeks) with median overall survival of 31.5 weeks (7–139 weeks).

Conclusions

G-FLIE is a tolerable multi-agent chemotherapy regimen with the oxaliplatin dose up to 85 mg/m². The combination of full-dose oxaliplatin with gemcitabine, irinotecan, and 5-fluorouracil is feasible with attenuated doses of the drugs, but further optimization is necessary before assessment of efficacy.     

Whither surgical quality assurance of breast cancer surgery (surgical margins and local recurrence) after paterson

Purpose

The randomized phase III JO21095 trial compared the efficacy and safety of low-dose capecitabine plus docetaxel combination therapy (XT) versus single-agent administration of docetaxel in anthracycline-pretreated HER2-negative metastatic breast cancer.

Methods

Patients were randomized to either low-dose XT (capecitabine 825 mg/m² twice daily, days 1–14; docetaxel 60 mg/m², day 1 every 3 weeks) or docetaxel (70 mg/m², day 1 every 3 weeks). The primary objective was to demonstrate superior progression-free survival (PFS) with low-dose XT versus single-agent docetaxel. Overall survival (OS) and safety were secondary endpoints.

Results

In total, 162 patients were treated. Median PFS was 10.5 months with low-dose XT and 9.8 months with single-agent docetaxel (hazard ratio [HR] 0.62 [95% confidence interval (CI) 0.40–0.97]; p = 0.03). The OS HR was 0.89 (95% CI 0.52–1.53; p = 0.68). Grade ≥3 treatment-related toxicities occurred in 74% of XT-treated patients and 76% of docetaxel-treated patients. The main differences in grade ≥3 treatment-related toxicities were hand-foot syndrome (7.3% of XT-treated patients vs 0% receiving docetaxel), fatigue/malaise (2.4 vs 10.0%), and peripheral edema (1.2 vs 7.5%). Dose modifications were required in 100% of low-dose XT and 49% of docetaxel patients. Toxicity-related treatment discontinuations occurred in 18 and 33%, respectively.

Conclusion

The improved PFS with low-dose XT versus docetaxel alone is consistent with higher-dose XT phase III experience, but the safety profile was more favorable and manageable.

     

Prolonged treatment with three-weekly docetaxel plus daily prednisolone for metastatic castration-resistant prostate cancer: a multicenter, phase II, open-label, non-comparative, extension study in Japan

Background

There are few reports of long-term treatment with docetaxel in castration-resistant prostate cancer (CRPC) because of the limit of a maximum of ten cycles of treatment in TAX327 showing a survival benefit. Therefore, this study, ARD6563, was conducted to evaluate the safety of more than ten cycles of docetaxel in metastatic CRPC.

Methods

We enrolled patients who had received ten cycles of docetaxel in the preceding study, ARD6562. For ARD6563, patients received docetaxel every 3 weeks, at the last dose (70, 60, or 50 mg/m²) received for cycle 10 in ARD6562, with prednisolone 5 mg orally twice daily.

Results

The safety analysis set comprised 15 patients (median age, 64 years; performance status, 0 in 87%) out of 43 patients treated in ARD6562. The median initial dose of docetaxel was 60 mg/m², and the median number of additional cycles administered was 8 (range, 1–42). The relative dose intensity was 78.0% for docetaxel and 98.0% for prednisolone. Dose reduction was needed in 3 cycles because of grade 3 infection, febrile neutropenia, and grade 2 neuropathy. Administration delay was necessitated in 6 cycles because of grade 1–2 nonhematological toxicities. The major grade 3–4 toxicities were myelosuppression. Five patients who had an observed partial response or stable disease in ARD6562 maintained their clinical response in ARD6563. The study treatment was discontinued in 10 patients because of disease progression and in 4 patients for serious toxicities. There were no treatment-related deaths.

Conclusions

Long-term docetaxel with prednisolone is feasible in selected Japanese patients with CRPC.     

A multi-center phase II study of docetaxel plus cisplatin as first-line therapy in patients with metastatic squamous cell esophageal cancer

Objective

The objective of this study was to evaluate the efficacy and toxicity of docetaxel and cisplatin combination chemotherapy in patients with metastatic esophageal cancer.

Methods

Patients with untreated metastatic squamous cell esophageal cancer, which was histologically proven with at least one measurable lesion, were eligible for the study. Docetaxel 70 mg/m² and cisplatin 70 mg/m² were intravenously given on day 1 of 21 days schedule.

Results

From December 2004 to December 2007, total of 39 patients (M/F = 39/0) were enrolled. The median age was 65 years. Thirty-four patients were evaluable for response. There were 3 (7.7%) complete remission, 10 (25.6%) partial remission, 11 (28.2%) stable disease, and 10 (25.6%) progression disease. The objective tumor response rate was 33.3% in intention-to-treat (ITT). Median PFS was 5.0 months and median survival was 8.3 months. Median number of cycles administered was 3. The relative dose intensity of docetaxel and cisplatin was 92 and 91%, respectively. This treatment was comparatively tolerated with grade 3/4 neutropenia in 20.5%/10.3%, grade 3 infection in 2.6% of patients.

Conclusion

Docetaxel plus cisplatin combination chemotherapy showed promising antitumor activity with manageable toxicities in patients with metastatic squamous esophageal cancer.     

Phase II study of short-course capecitabine plus oxaliplatin (XELOX) followed by maintenance capecitabine in advanced colorectal cancer: XelQuali study

Purpose

To evaluate the efficacy, safety and quality of life of a short course of oxaliplatin plus capecitabine (XELOX) followed by single-agent capecitabine in patients with previously untreated, inoperable, metastatic colorectal cancer.

Methods

Patients received intravenous oxaliplatin 130?mg/m² on d1 plus oral capecitabine 1,000?mg/m² twice daily (bid) on d1?C14 every 21?days for four cycles. Patients achieving stable disease (SD) or better than received capecitabine 1,250?mg/m² bid on d1?C14 every 21?days until disease progression. The primary endpoint was progression-free survival (PFS).

Results

Overall, 21/45 (47%) of patients responded to the initial XELOX chemotherapy whilst SD or better was documented in 76%. Median PFS was 6.7 (95% CI 5.7?C9.6) months, and median overall survival (OS) was 20.5 (95% CI 13.1?C28.1) months. In the 34 patients who then received capecitabine maintenance therapy, the median PFS was 8.1 (95% CI 6.2?C11.8) months and median OS was 23.1 (95% CI 17.8?C28.5) months. A marked reduction in the vast majority of all grades of adverse event occurred on switching from initial XELOX to maintenance capecitabine chemotherapy including grades 1?C2 (77 vs. 47%) and grade 3 (7 vs. 3%) neuropathy, diarrhoea and lethargy.

Conclusions

Short-course XELOX followed by capecitabine maintenance therapy provides an active and well-tolerated treatment option for patients with previously untreated metastatic colorectal cancer. A median OS of more than 20?months is promising and by limiting the number of oxaliplatin infusions, this approach minimises the risk of unwanted cumulative neurotoxicity, is cheaper and more convenient for both patients and healthcare providers.