Sequential chemotherapy with cisplatin, leucovorin, and 5-fluorouracil followed by docetaxel in previously untreated patients with metastatic gastric cancer: a phase II study

Background

The combination of docetaxel, cisplatin, and 5-fluorouracil (5-FU) has demonstrated a survival advantage over cisplatin and 5-FU, but with substantial hematological toxicity. We aimed to evaluate the efficacy and toxicity of a sequential regimen with cisplatin, leucovorin, and 5-FU (PLF) followed by docetaxel in metastatic gastric cancer patients.

Methods

Treatment consisted of 4 cycles of biweekly PLF (cisplatin 50?mg/m² as a 30-min infusion on day 1, leucovorin 200?mg/m² in a 2-h infusion, and 5-FU 2,800?mg/m² in a 48-h continuous infusion starting on day 1) followed, in cases of response or stable disease, by 3 cycles of docetaxel (75?mg/m², every 3?weeks).

Results

Thirty-four patients were enrolled, with an average age of 64?years (range 34–69). The main cumulative grade 3–4 toxicities were: neutropenia (38.2%), febrile neutropenia (11.8%), and fatigue (14.7%). After the planned 7 cycles of treatment, the overall response rate was 38.2% (95% confidence interval [CI] 21.9–54.6), with 3 complete and 10 partial responses. Median progression-free survival and overall survival were 4.8 and 10.6?months, respectively.

Conclusions

For patients with metastatic gastric cancer, the sequential administration of cisplatin, leucovorin, 5-FU, and docetaxel may be an effective palliative option and offers a far more favorable toxicity profile than the simultaneous use of docetaxel, cisplatin, and 5-FU.     

A lower dose of docetaxel at 60?mg/m2 could be continued longer for controlling peripheral edema in patients with metastatic breast cancer

Background

Docetaxel is a key drug for metastatic breast cancer (MBC). In patients with MBC, the treatment objective is durable response with minimum toxicity. In Japan, the approved dose of docetaxel is 60?C70?mg/m² every 3?weeks, whereas 75?C100?mg/m² docetaxel is common in the West.

Methods

We retrospectively examined the prevalence of edema in patients with MBC who were treated with docetaxel. Seventy-seven patients received docetaxel at a dose of 60?mg/m² every 3?weeks with prophylactic premedication of dexamethasone, 8?mg daily for 3?days.

Results

Median follow-up time was 28?months (range 4.3?C98). Overall response was 25% (95% CI 15?C34). Median time to progression and median survival time from the beginning of any systemic therapy for metastatic disease were 10 and 66?months, respectively. Neutropenia was the most common toxicity, with grade 3?C4 observed in 66%. Fifty-one percent of the patients experienced peripheral edema that could be controlled with oral diuretics. Grade 3 edema was observed in 4 patients only, and discontinuation because of edema was 9%. Other grade 3 or 4 toxicity was <5%. Median cumulative dose of docetaxel to onset of peripheral edema was 480?mg/m² (range 60?C780), and median cumulative given dose was 600?mg/m² (range 84?C2,928).

Conclusions

These results suggest that treatment with docetaxel at 60?mg/m² could be continued longer than the higher dose with manageable peripheral edema in patients with MBC. Further investigation is required to determine the superiority of low-dose docetaxel.     

Sequential chemotherapy with dose-dense docetaxel, cisplatin, folinic acid and 5-fluorouracil (TCF-dd) followed by combination of oxaliplatin, folinic acid, 5-fluorouracil and irinotecan (COFFI) in metastatic gastric cancer: results of a phase II trial

Purpose

To evaluate a new strategy of two sequential, intensified chemotherapy regimens in metastatic gastric cancer.

Patients and methods

Chemo-na?ve patients with metastatic gastric cancer were enrolled to receive 4 cycles of TCF-dd (docetaxel initially 85?mg/m² and cisplatin initially 75?mg/m² on day 1 [later modified due to toxicity: 70 and 60?mg/m² respectively], l-folinic acid 100?mg/m² on days 1 and 2, 5-fluorouracil 400?mg/m² bolus and then 600?mg/m² as a 22?h continuous infusion on day 1 and 2, every 14?days). Subsequently, patients with CR, PR or SD received 4 cycles of COFFI (oxaliplatin 85?mg/m², irinotecan 140?mg/m², l-folinic acid 200?mg/m², 5-fluorouracil bolus 400?mg/m² on day 1 followed by 2,400?mg/m² as a 48?h continuous infusion, every 14?days). In both regimens pegfilgrastim 6?mg subcutaneously on day 3 was included.

Results

Forty consecutive patients were enrolled. TCF-dd regimen achieved an ORR of 55% (95% CI, 40?C70). Twenty-three patients proceeded to COFFI. After this regimen the ORR was then increased to 60% (95% CI, 45?C75). Among the 21 patients treated with TCF-dd after the protocol amendments, main grade 3?C4 toxicities were: neutropenia (29%), thrombocytopenia (19%), asthenia (24%) and diarrhea (14%). COFFI caused grade 3?C4 neutropenia (all not febrile) and diarrhea in 35% and 17% of patients respectively.

Conclusions

A sequential strategy with TCF-dd followed by COFFI is very active and may be of special interest in selected patients.     

Phase I/II docetaxel plus concurrent hyperfractionated radiotherapy in locally advanced unresectable head and neck cancer (TAX.ES1.102 study)

Introduction

Concurrent chemotherapy and radiotherapy is recommended for the treatment of locally advanced unresectable head and neck (H&N) cancer.

Objective

The primary purpose of the Phase I part of the study was to determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT) and recommended dose (RD) of docetaxel with hyperfractionation radiotherapy. The primary objective of the Phase II part was to determine the response rate to the RD of treatment and, secondarily, to assess the toxicity of the schedule, time to progression, duration of response and overall survival (OS).

Materials and methods

Patients (n=9 in Phase I; n=19 in Phase II) had unresectable H&N cancer. The starting docetaxel dose was 20 mg/m² plus hyperfractionated radiotherapy. Ramping of docetaxel was 5 mg/m² if MTD was not reached.

Results

MTD of docetaxel was 20 mg/m². Limiting toxicities were grade 4 pneumonia and grade 4 mucositis. The RD was 15 mg/m2. Phase II initial response was 76% (CR=18%; PR=9%); updated response was 89% (CR=59%; PR=29%). The median progression-free survival was 7.8 months (95%CI: 0?C22.3) and the median OS was 15.1 months (95%CI: 0?C35.9). Grade 3?C4 toxicities included mucositis (91%), pneumonia (27%) and fatigue (27%). There were 5 toxic deaths (2 from intestinal perforation, 3 from pneumonia).

Conclusions

Weekly docetaxel+hyperfractionation radiotherapy is active but with high toxicity rates and, hence, this treatment regimen would be difficult to justify.     

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.     

Maintenance therapy with pemetrexed versus docetaxel after induction therapy with carboplatin and pemetrexed in chemotherapy-naïve patients with advanced non-squamous non-small-cell lung cancer: a randomized, phase II study

Purpose

The optimal strategy for maintenance chemotherapy is controversial. We evaluated the efficacy and safety of continuation maintenance with pemetrexed and switch maintenance with docetaxel in advanced non-squamous non-small-cell lung cancer (NSCLC).

Methods

Chemotherapy-naïve patients with non-squamous NSCLC were enrolled in this randomized phase II study. Patients who achieved disease control after four cycles of induction therapy with carboplatin (AUC 6) and pemetrexed (500 mg/m²) were randomized to maintenance therapy with pemetrexed (500 mg/m²) or docetaxel (60 mg/m²). The primary endpoint was survival without toxicity, defined as the time from the initiation of maintenance therapy to the first date of any grade 3/4 toxicity or death due to any cause.

Results

A total of eighty-five patients were enrolled in the induction phase, and 26 patients were assigned to the pemetrexed maintenance therapy and 25 patients were assigned to the docetaxel maintenance therapy. Survival without toxicity was significantly longer in the pemetrexed group (median 20.8 months, 95 % confidence interval (CI) 0.7–not estimable) than in the docetaxel group (median 0.5 months, 95 % CI 0.2–2.0, hazard ratio 0.36, 95 % CI 0.17–0.74).

Conclusions

Continuation maintenance with pemetrexed may be a feasible treatment option for patients with non-squamous NSCLC who have achieved disease control after induction therapy with carboplatin and pemetrexed. Switch maintenance with docetaxel may also be efficacious but frequently causes severe hematologic toxicity.     

A phase I study of the biomodulation of capecitabine by docetaxel and gemcitabine (mGTX) in previously untreated patients with metastatic adenocarcinoma of the pancreas

Background

Pancreas cancer remains a formidable challenge. We report the first prospective analysis of the 3-drug combination of gemcitabine (G), docetaxel (T) and capecitabine (X) (mGTX) with schedule modification to maximize biomodulation of X.

Methods

We conducted a dose escalation study of mGTX in first-line treatment of metastatic pancreas cancer using three dose levels (DL 1-3). Patients received docetaxel on days 1 and 8, gemcitabine on days 8 and 15, and capecitabine on days 8 through 21. Gemcitabine dose was fixed at 750?mg/m² over 75?min, capecitabine was given twice daily and escalated from 500 to 650?mg/m² at DL2 and docetaxel increased from 30 to 36?mg/m² at DL3.

Results

Twenty-one patients (18 evaluable) were enrolled in the study. MTD was reached at DL3 and one DLT was observed at DL2 (prolonged neutropenia). The most common grade 3/4 toxicities were leukopenia (29%) and neutropenia (29%) and fatigue (25%). Tumor growth control rate was 80% (11% PR; 69% SD lasting at least 3?months). Median progression-free-survival was 5.8?months (95% CI 2.7, 10.6) and median overall survival was 7.4?months (95% CI 3.8 16.8). CA 19-9 decreased by at least 50% from baseline in half the patients.

Conclusion

mGTX demonstrates acceptable tolerability with interesting activity in patients with pancreatic cancer. The recommended doses for phase II studies are docetaxel 36?mg/m² days 1 and 8, gemcitabine 750?mg/m² over 75?min days 8 and 15, and capecitabine 625?mg/m² twice daily days 8 through 21.     

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.     

Chemotherapy with gemcitabine, cisplatin, and docetaxel in the treatment for patients with muscle-invasive bladder cancer: a multicenter phase II study of the Hellenic Oncology Research Group (HORG)

Purpose

To assess the antitumor activity and toxicity of gemcitabine, cisplatin, and docetaxel (GCD) regimen in patients with locally advanced or metastatic urothelial cancer.

Patient and methods

Chemotherapy-na?ve patients, aged ??70?years with measurable or evaluable disease and a performance status (PS) of 0?C2 were treated with sequential cisplatin 80?mg/m² (d1), gemcitabine 1,100?mg/m² (d1 and d14), and docetaxel 80?mg/m² (d14) every 28?days.

Results

Sixty patients with an ECOG PS of 0?C2 were enroled. Most (71.7%) patients had stage IV disease. A median number of 4 chemotherapy cycles per patient (range, 1?C9) was administered. Eight (13.3%) patients achieved a CR and 16 (26.7%) a partial response (PR) (intention-to-treat: ORR 40%; 95% CI 27.6?C52.4%). Thirteen (21.7%) and 23 (38.3%) patients experienced stable and progressive disease, respectively. The median time to progression (TTP) was 7.7?months (range, 0.7?C43.4), and the median overall survival 21.4?months (range, 0.7?C68.6). Grade 3 and 4 neutropenia occurred in 27 (45%) patients and grade 3 and 4 thrombocytopenia in five (8.3%). Three (5%) patients developed febrile neutropenia. There were no treatment-related deaths. Severe non-haematological toxicity was infrequent.

Conclusions

The GCD combination is an active and well-tolerated regimen in patients with chemotherapy-naive locally advanced or metastatic TCC and merits to be further investigated.     

Randomized trial of weekly docetaxel and cisplatin combined with concurrent 3DCRT in patients with locally advanced esophageal cancer

Objective

This randomized controlled clinical study was to assess and compare the efficacy and safety of two chemoradiotherapy regimens [cisplatin + 5-fluorouracil + 3 dimensional conformal radiation therapy (3DCRT) and cisplatin + weekly docetaxel + 3DCRT] in patients with locally advanced esophageal squamous cell carcinoma.

Methods

A total of seventy-four patients with clinical stages IIB to IIIB esophageal squamous cell carcinoma were enrolled. Chemotherapy for PF group comprised 5-fluorouracil at days 1–5 (250 mg/m²/d) and cisplatin (20 mg/m²) at days 1–3 of every 28-day cycle; full treatment course included 2 cycles. Chemotherapy for DP group comprised docetaxel (20 mg/m²) and cisplatin (20 mg/m²) at days 1, 8, 15, 22, 29, and 36. Both groups treated with concurrent 60 Gy 3DCRT at 200 cGy/d.

Results

Seventy-four patients were enrolled and 71 completed the planned treatment, with a follow-up rate of 95.94%. Short-term curative effect was not statistically significant between the two groups (P = 0.471). The 2-year survival rates were 65.7% and 61.1%, respectively (P = 0.806), 5 years survival rates were 34.29% and 27.78%, respectively (P = 0.221), and there was no significant difference by Fisher test (P = 0.734). As common side effects, incidence rates of radioactive esophagitis and hematological toxicity were lower in DP group.

Conclusion

For locally advanced esophageal cancer patients, current chemoradiotherapy with chemotherapy regimen of weekly docetaxel plus cisplatin has equal curative effect with 5-fluorouracil plus cisplatin, but well-tolerated by reducing side effects such as radioactive esophagitis and bone marrow suppression.     

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.     

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.     

Docetaxel,oxaliplatin, and capecitabine combination chemotherapy for metastatic gastric cancer

Background

The incorporation of docetaxel into the cisplatin and fluorouracil backbone has been demonstrated to be an active combination in metastatic gastric cancer. Nevertheless, this regimen is burdened by nonnegligible toxicity. We hypothesized that replacing cisplatin and fluorouracil with oxaliplatin and capecitabine should be an active and safe option for metastatic gastric cancer patients.

Methods

In this phase II study, we tested the activity of docetaxel in combination with oxaliplatin and capecitabine (DOC) as a first-line treatment. DOC was administered as follows: docetaxel (60 mg/m²) and oxaliplatin (100 mg/m²) on day 1, and capecitabine (500 mg/m²) was administered orally twice daily given continuously, with cycles repeated every 3 weeks. The primary endpoint was the overall response rate.

Results

Forty-eight patients entered the study. All patients had metastatic disease (stage IV). None of the patients had previously received chemotherapy for advanced disease. Performance status was 0, 1, and 2 in 25, 58, and 17 % of patients, respectively; 13 patients (27 %) had adenocarcinoma of the gastroesophageal junction, and 29 patients (60.5 %) had two or more metastatic sites. The overall response rate was 52.1 %. Progression-free survival and overall survival were 6.9 and 12.6 months, respectively. The treatment was well tolerated with no treatment-related deaths. The most common grade 3–4 toxicity was neutropenia (41 %).

Conclusions

DOC is an effective and tolerated first-line treatment, and the lower dose of docetaxel and oxaliplatin used in this study compared with other similar regimens does not seem to hamper the antitumor activity.     

Efficacy and toxicity of concurrent chemoradiotherapy in patients with advanced oropharyngeal squamous cell carcinoma

Purpose

The aim of this study was to evaluate the feasibility and toxicity of concurrent chemoradiotherapy (CCRT) with docetaxel, cisplatin (CDDP) and 5-fluorouracil (5-FU) (TPF regimen) or with CDDP, 5-FU, methotrexate and leucovorin (PFML regimen) in previously untreated patients with advanced oropharyngeal squamous cell carcinoma (SCC).

Methods

Fifty-six eligible patients with stage III or IV oropharyngeal SCC were treated with CCRT. Forty-four patients were men and 12 were women, and the average age of the patients was 58.8?years (range, 37?C72?years). In the TPF group, patients received CCRT with the TPF regimen [docetaxel (50?mg/m², day 1), CDDP (60?mg/m², day 4) and a continuous 5-FU infusion (600?mg/m²/day, days 1?C5)]. In the PFML group, patients received CCRT with the PFML regimen [CDDP (60?mg/m², day 4), a continuous 5-FU infusion (600?mg/m²/day, days 1?C5), methotrexate (30?mg/m², day 1) and leucovorin (10?mg/m²/day, days 1?C5)]. The total radiation dose was between 66.6 and 70.2?Gy.

Results

The overall 5-year survival rate was 64.6% in all patients, 68.6% in the resectable group and 47.4% in the unresectable group. The 5-year disease-specific survival rate was 72.2% in all patients, 78.1% in the resectable group and 47.7% in the unresectable group. Regarding clinical stage, the 5-year disease-specific survival rates were 91% in stage III, 72% in stage IVa and 44% in stage IVb.

Conclusion

CCRT with TPF or PFML regimen for advanced oropharyngeal SCC is tolerable and effective, especially in patients with resectable disease.     

Phase II study of docetaxel, cisplatin, and 5-FU induction chemotherapy followed by chemoradiotherapy in locoregionally advanced nasopharyngeal cancer

Purpose

This study sought to determine the feasibility and safety of induction chemotherapy with docetaxel, cisplatin, and 5-fluorouracil (5-FU) triple combination chemotherapy (TPF) followed by concurrent chemoradiotherapy (CCRT) for locoregionally advanced nasopharyngeal cancer (NPC).

Methods

Patients with advanced NPC were treated with three cycles of induction chemotherapy. Docetaxel (70 mg/m²) and cisplatin (75 mg/m²) were given on day 1, followed by 5-FU (1,000 mg/m²) as a continuous infusion for 4 days. After induction chemotherapy, cisplatin was given at a dose of 100 mg/m² every 3 weeks with radiotherapy.

Results

Thirty-three patients were enrolled; all patients were stage III (n = 4, 12.1%) or IV (n = 29, 87.9%). Among the patients, 32 patients completed both induction TPF therapy and CCRT, with responses as follows: five patients (15.2%) achieved a complete response (CR), and 27 patients (81.8%) a partial response (PR). At 6 weeks after CCRT, 23 patients (69.7%) had a CR and 9 patients (27.3%) a PR. The 3-year progression-free survival was 75.6% and the 3-year overall survival was 86.1%. Neutropenia (72.7%), febrile neutropenia (9.1%), and nausea (9.1%) were the most severe toxicities (grade 3–4) during induction chemotherapy, and mucositis (39.4%), fatigue (15.2%), and nausea (9.1%) were the most common toxicities (grade 3–4) during CCRT.

Conclusions

Although most patients had stage IV NPC, the TPF induction chemotherapy followed by CCRT showed promising activity with manageable toxicity. These results demonstrated the possibility of effective treatment with the aim of not only a palliative, but also a curative, approach to the treatment of advanced NPC.     

Phase I and pharmacokinetic study of erlotinib (OSI-774) in combination with docetaxel in squamous cell carcinoma of the head and neck (SSCHN)

Purpose

This phase I study determined the maximal-tolerated dose, dose-limiting toxicities, pharmacokinetics, and recommended dose of erlotinib with docetaxel.

Patients and methods

Twenty-eight patients with head and neck cancer were enrolled. Patients were orally given erlotinib (50?mg) daily plus 35?mg/m² of docetaxel intravenously weekly?×?3 every 4?weeks. Dose escalation of erlotinib was in 50-mg increments until toxicity. Pharmacokinetics were studied with LC?CMS/MS, standard, and population pharmacokinetic methods.

Results

Ninety-five courses were successfully given (median 3, range 1?C6). The most frequent side effects were diarrhea, fatigue, skin rash, anemia, and hypoalbuminemia. Dose de-escalation for both erlotinib and docetaxel was due to skin rash, neutropenia and/or severe infection with docetaxel to 25?mg/m² and erlotinib to starting dose of 50?mg and re-escalation of docetaxel to 35?mg/m². Responses were observed in 4/26 evaluable patients (100?mg erlotinib). In 24 patients, the mean Cmax and AUC erlotinib values increased with dose and following cumulative dosing (days 7 and 8 vs. day1, p?<?0.05). The CL/F (~7 L/h), V/F (~140?L), and t1/2 (~20?h) for erlotinib were similar to the reported. The mean AUC ratio of metabolite OSI-420 to erlotinib following repetitive dosing at 100?mg (+?or ?C?docetaxel) showed a ~50% increase (p?<?0.02), possibly suggesting self-enzyme induction. Population pharmacokinetic studies showed no significant covariate affecting erlotinib pharmacokinetics.

Conclusions

The combination of erlotinib and docetaxel was associated with significant toxicity, which limited the amount of administered erlotinib. Dosing for phase II trials was docetaxel 35?mg/m² and erlotinib 50?mg. The reason for excessive toxicity is not clear, but not due to change in pharmacokinetics.     

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.     

A multicenter phase II study of combined chemotherapy with docetaxel, cisplatin, and S-1 in patients with unresectable or recurrent gastric cancer (KDOG 0601)

Purpose

We conducted a phase II study to evaluate the efficacy and safety of a triplet regimen of docetaxel, cisplatin, and S-1 in patients with unresectable or recurrent gastric cancer.

Methods

Docetaxel (40?mg/m²) and cisplatin (70 or 60?mg/m²) were given on day 1 of a 28-day cycle. S-1 (40?mg/m²) was given twice daily on days 1?C14. Treatment with this regimen was continued for a maximum of 6 cycles. Subsequently, patients with no disease progression received a combination of docetaxel and S-1.

Results

Fifty-nine patients were enrolled. The median number of administered cycles was 8 (range, 1?C25). Because some patients had serious myelosuppression and renal dysfunction with 70?mg/m² of cisplatin, dose of cisplatin was reduced to 60?mg/m² after 19 patients had been treated. Common severe toxic effects of grade 3 or 4 were leukocytopenia (44%), neutropenia (72%), anemia (15%), and febrile neutropenia (14%). The overall response rate of this group was 81% (95% confidence interval (CI), 71?C91%). The median overall survival and progression-free survival were 18.5 (95% CI, 15.6?C21.5) and 8.7 (95% CI, 6.7?C10.7) months, respectively.

Conclusions

Triplet of docetaxel, cisplatin, and S-1 is a well-tolerated and highly active regimen for advanced or recurrent gastric cancer. A 60?mg/m² of cisplatin is as effective as 70?mg/m² of cisplatin.     

Phase I/II study of intraperitoneal docetaxel plus S-1 for the gastric cancer patients with peritoneal carcinomatosis

Purpose

We designed a phase I/II trial of intraperitoneal (IP) docetaxel plus S-1 to determine the maximum tolerated dose (MTD) and recommended dose (RD) and to evaluate its efficacy and safety in gastric cancer patients with peritoneal carcinomatosis (PC).

Methods

Patients with PC confirmed by laparoscopy or laparotomy received IP docetaxel on days 1 and 15 and S-1 (80 mg/m²) on days 1–14 every 4 weeks.

Results

In the phase I part (n = 12), each cohort received escalating doses of docetaxel (35–50 mg/m²); the MTD was determined to be 50 mg/m² and the RD was determined to be 45 mg/m². Dose-limiting toxicities included grade 3 febrile neutropenia and grade 3 diarrhea. In the phase II part (n = 27), the median number of courses was 4 (range 2–11). The 1-year overall survival (OS) rate was 70 % (95 % confidence interval 53–87 %). The overall response rate was 22 % and peritoneal cytology turned negative in 18 of 22 (81 %) patients. The most frequent grade 3/4 toxicities included anorexia (19 %), neutropenia (7 %), and leukopenia (7 %).

Conclusion

IP docetaxel plus S-1 is active and safety in gastric cancer patients with PC.