Randomized controlled phase II comparison study of concurrent chemoradiotherapy with docetaxel, cisplatin, and 5-fluorouracil versus CCRT with cisplatin, 5-fluorouracil, methotrexate and leucovorin in patients with locally advanced squamous cell carcinoma of the head and neck

We compared concurrent chemoradiotherapy (CCRT) with docetaxel, cisplatin (CDDP), and 5-fluorouracil (5-FU) (TPF) with CCRT with CDDP, 5-FU, methotrexate and leucovorin (PFML) in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN) in terms of safety and efficacy on survival. A total of 100 patients were enrolled. The TPF group received CCRT with the TPF regimen [docetaxel (50 mg/m²: day 1), CDDP (60 mg/m²: day 4), and continuous 5-FU infusion (600 mg/m²/day: days 1–5)]. In the PFML group, patients received CCRT with the PFML regimen [CDDP (60 mg/m²: day 4)], continuous 5-FU infusion (600 mg/m²/day: days 1–5), methotrexate (30 mg/m²: day 1) and leucovorin (20 mg/m²/day: days 1–5)]. Both groups received 2 cycles of chemotherapy during definitive radiotherapy. The total radiation dose was between 66.6 and 70.2 Gray. The overall response rates after CCRT were 98 with 90% of a pathologically complete response (pCR) in the TPF group and 94 with 77% in the PFML group. For grade 3/4 adverse events, mucositis was more frequent in the PMFL group, and the TPF group showed a higher incidence of hematological toxicity. CCRT with TPF or PMFL for advanced SCCHN was tolerable and produced excellent survival rates.     

Concurrent chemoradiation followed by adjuvant chemotherapy in patients with locoregionally advanced nasopharyngeal carcinoma in Korea

Purpose

Concomitant approach using cisplatin and 5-fluorouracil (5-FU) has shown an excellent local control rate and significantly reduced distant metastasis in patients with locally advanced nasopharyngeal carcinoma (NPC). However, optimal schedule and dosing of chemotherapy still need to be developed to reduce distant metastasis. This retrospective study was conducted to evaluate the efficacy, toxicity, and tolerability of a concurrent chemoradiation therapy (CCRT) regimen using cisplatin and 5-FU followed by adjuvant chemotherapy (AC) in patients with locoregioanlly advanced NPC.

Methods

Forty-three NPC patients who had AJCC stage T3/T4 or N2/N3 and M0 disease were evaluated. The chemotherapy during CCRT consisted of cisplatin (75 mg/m² on day 1) plus 5-FU (750 mg/m²/day on day 1–5), delivered every 4 weeks for two cycles. Three cycles of AC were given with cisplatin (75 mg/m²), epirubicin (37.5 mg/m²) on day 1, and bleomycin (7.5 mg/m² bolus iv. on day 1 followed by 9 mg/m² on day 1–5 by continuous infusion) every 3 weeks.

Results

The overall response rate after CCRT was 95% (22 CRs and 19 PRs in 43) and 100% (16 CRs and 8 PRs in 24) after AC. Grade 3/4 neutropenia, mucositis, and weight loss were observed during CCRT phase in 18, 44, and 26% of patients, respectively. AC caused grade 3/4 neutropenia and emesis in 12.5 and 20.8% of patients, respectively.

Conclusions

CCRT regimen using cisplatin and 5-FU followed by three cycles of BEC chemotherapy was effective in locally advanced NPC patients, with acceptable and reversible acute toxicities.     

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 II study of FOLFIRI regimen in patients with advanced colorectal cancer refractory to fluoropyrimidine and oxaliplatin

Purpose

To evaluate the efficacy and safety of FOLFIRI regimen in patients with advanced colorectal cancer refractory to fluoropyrimidine and oxaliplatin.

Methods

The FOLFIRI regimen consisted of intravenous infusion of irinotecan 180?mg/m² on day 1 plus leucovorin (LV) 400?mg/m² on day 1 plus 5-fluorouracil (5-FU) 400?mg/m² bolus on day 1 plus 46-hour intravenous infusion of 5-FU 2,400?mg/m², every 2?weeks as one cycle. The main selection criterion for this study was the advanced colorectal cancer refractory to fluoropyrimidine and oxaliplatin.

Results

Of the 57 evaluable patients for efficacy, 4 (7.5%) had a partial response, 36 (67.9%) had stable disease, and 13 (24.5%) had progressive disease. Median progression-free survival was 4.8?months (95% CI 3.9?C5.7?months), and median overall survival was 7.8?months (95% CI 13.1?C16.5?months). Safety analysis was based on the data of 57 evaluable patients. The most frequently observed grade 3 or 4 toxicities were neutropenia 16 (27.8%), nausea/vomiting 7 (12.3%), and diarrhea 1 (1.8%).

Conclusion

FOLFIRI regimen is effective and well tolerated in patients with advanced colorectal cancer refractory to fluoropyrimidine and oxaliplatin in Chinese population.     

Analysis of efficacy and toxicity of chemotherapy with cisplatin, 5-fluorouracil, methotrexate and leucovorin (PFML) and radiotherapy in the treatment of locally advanced squamous cell carcinoma of the head and neck

Purpose The aim of this study was to evaluate the efficacy and toxicity of concurrent chemoradiotherapy using cisplatin (CDDP), 5-fluorouracil (5-FU), methotrexate (MTX) and leucovorin (LV) (PFML) in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN). Methods Seventy-seven patients with previously untreated stages III–IV SCCHN were included in this trial. Patients received two cycles of chemotherapy repeated every 4 weeks. The chemotherapy regimen consisted CDDP (60 mg/m², day 4), 5-FU (600 mg/m² given over 24 h for 5 days, days 1–5), MTX (30 mg/m², day 1) and LV (20 mg/m², days 1–5). Radiation was targeted to begin on the starting day of chemotherapy, day 1. The total radiation dose to the primary site and neck lymph nodes was 70.0 Gy. When grade ≥3 toxicities were observed frequently, radiotherapy and/or chemotherapy were delayed or reduced. Results The main toxicities were mucositis (grade ≥3, 39%), leukocytopenia (grade ≥3, 34%) and neutropenia (grade ≥3, 30%). The overall clinical response rate and the pathological complete response (CR) were 94% (72/77) and 71% (55/77). The primary site CR and neck lymph node CR were 79% (61/77) and 85% (44/52), and 3-year survival rate was 73%. Conclusions This concurrent chemoradiotherapy with PFML was safe and well tolerated. The high CR rate justifies further evaluation of this chemoradiotherapy modality in locally advanced SCCHN patients.     

Concurrent chemoradiotherapy with protracted infusion of 5-fluorouracil (5-FU) and cisplatin for locally advanced resectable esophageal cancer

Background

Neoadjuvant concurrent chemoradiotherapy (CCRT) has become the standard treatment for esophageal cancer (EC) in North America. The cisplatin/5-flurouracil (5-FU) combination has been the most commonly used regimen. For the last 15 years we incorporated a daily continuous infusion of 5-FU and 2 doses of cisplatin into our neoadjuvant CCRT for potentially resectable EC.

Patients and methods

Between July 1997 and June 2012, 129 patients with locally advanced EC (T3 or N1 and higher), received neoadjuvant CCRT with cisplatin 75 mg/m² on day 1 and day 29 and continuous infusion of 5-FU (225 mg/m²/day) on the days of radiation.

Results

The median age of patients was 63 years, 85% had adenocarcinoma, 29, 74 and 26 patients had stage II, III and IVa disease respectively, 110 patients had N1 disease based on the American Joint Committee on Cancer (AJCC) 6^th edition, 118 patients experienced weight loss during treatment. All patients completed treatment. Treatment was well tolerated with 14% of patients having ≥ grade 3 toxicity and 18 patients requiring hospital admission. Sixty-four percent of patients had surgical resection following CCRT, with disease progression and patient refusal being the most common reasons for not proceeding with surgery. An R0 resection was achieved in 96% of patients. A pathological complete response (pCR) was achieved in 45% of patients. With a median follow up of 26 months (1.2-144 months), 48/129 patients recurred and 60/129 died of their disease.

Conclusions

Our study has its limitation, however, and compared to the conventional chemotherapy regimens containing the cisplatin/5-FU doublet, our treatment strategy for locally advanced EC CCRT seems to be feasible and well tolerated.     

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 phase I study of paclitaxel, cisplatin, and fluorouracil (TCF) for advanced gastric cancer

Purpose

A phase I study of TCF therapy, which consists of paclitaxel (TXL: Taxol^®) + cisplatin (CDDP) + 5-fluorouracil (5-FU), in advanced gastric cancer patients was performed to determine the recommended dose (RD) for a phase II study by checking the dose-limiting toxicity (DLT) and maximum-tolerated dose (MTD) of 5-FU above the fixed dose of TXL and CDDP.

Methods

The doses of TXL and CDDP were fixed at 80 and 25 mg/m², respectively, while that of 5-FU was increased by 100 mg/m² in each cohort from 300 mg/m² (level 1) to a maximum of 600 mg/m² (level 4). One cycle consisted of administration of these agents once per week for 3 weeks, every 4 weeks.

Results

A total of twelve eligible patients were included in this study. At level 1, two of three cases showed grade 3 leukopenia. At level 2, one of three cases showed grade 4 neutropenia (recovered within 3 days), and another one case showed grade 3 neutropenia. At level 3, one of three cases showed grade 3 neutropenia, and at level 4, one of three cases showed grade 4 neutropenia (recovered within 3 days), with grade 3 neutropenia in the other two cases. Even at the highest dose administered, none of the patients showed DLT. Moreover, no non-hematological toxicity judged to be DLT was observed through all levels. Six of the twelve patients had measurable disease, and the overall response rate was 83%.

Conclusions

Although the MTD level was not determined, based on the observed efficacy and the results of other clinical trials, the recommended doses of TXL, CDDP, and 5-FU for the TCF regimen were set as 80, 25, and 600 mg/m², respectively, and a phase II study to investigate the clinical effectiveness and safety of this regimen has now begun.     

The efficacy of concurrent cisplatin and 5-flurouracil chemotherapy and radiation therapy for locally advanced cancer of the uterine cervix

Objective

To evaluate the efficacy of concurrent chemoradiation (CCRT) using 5-flurouracil (5-FU) and cisplatin for locally advanced cervical cancer.

Methods

We reviewed the medical records of 57 patients with locally advanced cervical cancer (stage IIB-IVA and bulky IB2-IIA tumor) who underwent the CCRT at Dong-A University Hospital from January 1997 to June 2007. The CCRT consisted of 5-FU, cisplatin and pelvic radiation. Every three weeks, 75 mg/m² cisplatin was administered on the first day of each cycle and 5-FU was infused at the dose of 1,000 mg/m²/d from the second day to the fifth day of each cycle. Radiation was administered to the pelvis at a daily dose of 1.8 Gy for five days per week until a medium accumulated dose reached to 50.4 Gy. If necessary, the radiation field was extended to include paraaortic lymph nodes. Consolidation chemotherapy was performed using 5-FU and cisplatin.

Results

Fifty-seven patients were enrolled and the median follow-up duration was 53 months (range 7-120 months). The overall response rate was 91.5% (74% complete response and 17.5% partial response). The 5-year overall survival and 3-year progression free survival rates were 69.4% and 74.9%, respectively. During the follow-up period (median 23 months, range 7-60 months), fourteen patients were diagnosed as recurrent disease.

Conclusion

CCRT with 5-FU and cisplatin which is the primary treatment for patients with locally advanced cervical cancer was effective and well tolerated.     

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.     

A phase I study of sorafenib in combination with S-1 plus cisplatin in patients with advanced gastric cancer

Background

Sorafenib inhibits several receptor tyrosine kinases involved in tumor progression and angiogenesis. S-1, an oral fluorouracil antitumor drug, plus cisplatin (CDDP) is the standard regimen for advanced gastric adenocarcinoma (AGC) in Japan. The purpose of this phase I study was to evaluate the safety, pharmacokinetics, and preliminary efficacy of sorafenib in combination with S-1 plus CDDP.

Methods

Patients with histologically confirmed previously untreated AGC were evaluated for eligibility and treated with sorafenib (400 mg bid, days 1–35), S-1 (40 mg/m² bid, days 1–21), and CDDP (60 mg/m², day 8). Treatment was continued until disease progression or unacceptable toxicity. Pharmacokinetics for sorafenib, 5-FU, and CDDP were investigated in cycle 1.

Results

Thirteen patients were enrolled and received at least one dose of the study treatment. No specific or serious adverse event was newly reported in this study. Five patients had partial response and 8 had stable disease as the best response. Pharmacokinetic analysis showed no significant differences in the exposures of sorafenib when administered alone or in combination with S-1 and CDDP.

Conclusions

The present phase I study demonstrates the acceptable toxicity and preliminary efficacy of combined treatment with S-1, CDDP, and sorafenib.     

Irinotecan combined with 5-fluorouracil and leucovorin third-line chemotherapy after failure of fluoropyrimidine, platinum, and taxane in gastric cancer: treatment outcomes and a prognostic model to predict survival

Background

The aim of this study was to evaluate the activity and safety of the combination chemotherapy of 5-fluorouracil (5-FU), leucovorin, and irinotecan (FOLFIRI regimen) after failure of fluoropyrimidine, platinum, and taxane in gastric cancer (GC) and to evaluate the prognostic factors for survival.

Methods

Patients received biweekly FOLFIRI chemotherapy as third-line treatment. The FOLFIRI-1 consisted of irinotecan (180 mg/m² in a 2-h infusion) on day 1, and then leucovorin (200 mg/m² in a 2-h infusion) and 5-FU (a 400 mg/m² bolus, followed by 600 mg/m² in a 22-h continuous infusion) on days 1 and 2. FOLFIRI-2 consisted of irinotecan (180 mg/m² in a 2-h infusion) on day 1, and then leucovorin (400 mg/m² in a 2-h infusion) and 5-FU (a 400 mg/m² bolus, followed by 2400 mg/m² in a 46-h continuous infusion) on day 1.

Results

A total of 158 patients were included. The overall response rate was 9.6 % in patients with measurable lesions. The median progression-free survival (PFS) and overall survival (OS) were 2.1 months [95 % confidence interval (CI), 1.7–2.5] and 5.6 months (95 % CI, 4.7–6.5), respectively. The major grade 3/4 toxicity was myelosuppression (36.7 %). Good performance status (PS), fewer metastatic sites, and longer duration from the first-line to third-line chemotherapy were independent prognostic factors affecting both PFS and OS.

Conclusions

The FOLFIRI regimen showed antitumor activity and tolerable toxicity profiles against advanced GC in the third-line setting. Patients with good PS, fewer metastatic sites and longer previous treatment duration might have the maximal benefit from third-line chemotherapy.     

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.     

Comparative analysis of the efficacy and safety of chemotherapy with oxaliplatin plus fluorouracil/leucovorin between elderly patients over 65?years and younger patients with advanced gastric cancer

Background

A chemotherapy regimen with oxaliplatin, fluorouracil, and leucovorin is commonly used to treat advanced gastric cancer (AGC). This study was designed to compare the efficacy and the safety of oxaliplatin plus fluorouracil/leucovorin administered biweekly (mFOLFOX6) between elderly patients aged over 65?years and younger counterparts with AGC.

Methods

This analysis included 82 AGC patients (≥65:31, <65:51). Patients with previously untreated chemo-na?ve advanced adenocarcinoma of the stomach received oxaliplatin 85?mg/m², 5-FU bolus 400?mg/m² on day?1 and 5-FU 1,500?mg/m², leucovorin 75?mg/m² 22?h infusion on days?1 and 2 every 2?weeks. The aim of the study was to compare efficacy and safety, including response rate (RR), progression-free survival (PFS), overall survival, and grade ≥3 adverse events, between patients aged ≥65 years and patients aged <65 years.

Results

Median progression-free survival (PFS) was not significantly different between both groups (≥65: 5.8?months, <65: 5.7?months, respectively, HR 0.77, 95% CI: 0.44–1.16, P?=?0.18). Median overall survival was not significantly different between both groups (≥65: 10.3?months, <65: 9.5?months HR 0.83, 95% CI: 0.50–1.37, P?=?0.46). The rate of grade 3 or 4 neutropenia did not differ with age group (≥65: 51.6%, <65: 43.1%); nor did the rates of neutropenic fever (≥65: 16.1%, <65: 5.9%), and infection without neutropenia (≥65: 3.2%, <65: 3.9%). Rates of grade ≥3 toxicities such as thrombocytopenia, nausea/vomiting, or peripheral neuropathy were not significantly different between the two groups.

Conclusions

mFOLFOX6 maintains its efficacy and safety in elderly patients aged over 65?years in comparison with AGC patients aged <65 years. Its judicious use should be considered regardless of age.     

Biweekly docetaxel, cisplatin, and 5-fluorouracil (DCF) chemotherapy for advanced esophageal squamous cell carcinoma: a phase I dose-escalation study

Background and purpose

The optimal chemotherapeutic protocol for the treatment of esophageal cancer has not yet been established. A dose-escalation study of docetaxel combined with cisplatin and 5-fluorouracil (5-FU) was performed to determine the optimal dose in patients with advanced esophageal squamous cell carcinoma.

Patients and method

We studied a total of 18 patients who had previously untreated thoracic esophageal squamous cell carcinoma with T4 tumors and/or metastasis. The patients received an infusion of docetaxel at different dose levels (levels 1, 2, 3: 30, 35, 40 mg/m², respectively) and an infusion of cisplatin (40 mg/m²) on days 1 and 15 plus a continuous infusion of 5-FU (400 mg/m²/day) on days 1–5 and 15–19.

Results

Dose-limiting toxicities (DLT) included febrile neutropenia and leukopenia. DLT occurred in 2 of 6 patients at level 1, 2 and in 3 of 6 patients at level 3. The response rate was 88.9%, including a complete response rate of 33.3%.

Conclusions

To minimize toxicity and maximize dose intensity, we elected to investigate a biweekly regimen. The maximum tolerated dose was level 3, and the recommended dose was determined to be docetaxel 35 mg/m² with cisplatin 40 mg/m² plus 5-FU 400 mg/m², administered biweekly. This regimen was tolerable and highly active. A phase II study has been started.     

Phase I dose-escalating study of 24-h continuous infusion of 5-fluorouracil in combination with weekly docetaxel and cisplatin in patients with advanced gastric cancer

Purpose

To determine the maximum-tolerated dose (MTD) of a 24-h continuous infusion of 5-fluorouracil (5-FU) when administered in combination with a fixed weekly dose of docetaxel and cisplatin in patients with advanced gastric cancer.

Methods

Patients with advanced gastric adenocarcinoma (n = 21) received a weekly regimen of docetaxel, cisplatin and 5-FU (DCF) for 3 consecutive weeks every 4 weeks. The doses of docetaxel and cisplatin were fixed at 33.3 and 30 mg/m², respectively. The dose of 5-FU was increased from a starting dose of 1,000 mg/m² to the MTD.

Results

A total of 53 cycles of chemotherapy were administered (median = 3 cycles/patient). The MTD of 5-FU was 1,750 mg/m². All 21 patients were assessed for toxicity and 19 patients (90%) were evaluated for response. Both grade 3–4 hematologic and non-hematologic toxicities occurred in less than 10% of patients and there were no treatment-related deaths. Among the 19 patients, we observed 1 complete and 4 partial responses for an overall response rate of 26% (95% CI: 6–46%). This rate increased to 39% (95% CI: 12–66%) in 13 chemotherapy-naïve patients.

Conclusions

A consecutive weekly DCF regimen at 4-week intervals appears feasible for advanced gastric cancer with a favorable toxicity profile. The recommended doses are 33.3 mg/m² of docetaxel, 30 mg/m² of cisplatin and 1,500 mg/m² of a 24-h continuous intravenous infusion of 5-FU. The response of this weekly regimen in our study was favorable and deserved further investigation in a phase II trial.     

Effectiveness of pharmacokinetic modulating chemotherapy combined with cisplatin as induction chemotherapy in resectable locally advanced head and neck cancer: phase II study

Purpose

To test the efficacy and safety of pharmacokinetic modulating chemotherapy combined with cisplatin (PMC-cisplatin) as induction chemotherapy (ICT) before definitive treatment in patients with respectable locally advanced head and neck squamous cell carcinoma (HNSCC).

Patients and methods

Patients with stage III–IV resectable locally advanced HNSCC were enrolled. All eligible patients received PMC-cisplatin regimen as ICT containing intravenous leucovorin 250 mg/m² and 5-FU 600 mg/m² on day 1, oral tegafur–uracil (UFUR^®) 250 mg/m²/day on days 1–5, repeated every week for six courses. Cisplatin 100 mg/m² was given during the first and fourth courses of PMC. For ICT responders, concurrent chemoradiotherapy (CRT) with cisplatin/tegafur–uracil/70 Gy radiotherapy was performed. Salvage surgery plus postoperative CRT was given to ICT non-responders.

Results

The overall response rate of PMC-cisplatin as ICT was 76%, including a complete remission rate of 23%. The overall organ preservation rate of the multimodality treatment was 75%, with 97% in ICT responders. At a median follow-up of 25 months, 47% of the patients were still alive and disease-free. The superiority of disease-free survival was demonstrated in ICT responders. The 3-year overall survival rate was 67%. The toxicity of treatment was acceptable.

Conclusions

Application of PMC-cisplatin as the induction chemotherapy before definitive treatment provides a promising result in treatment response and survival of advanced HNSCC. This regimen is effective and safe, and further studies considering the combination of PMC with other chemotherapeutics such as taxanes to improve the clinical outcome of advanced HNSCC is warranted.     

Neoadjuvant chemoradiotherapy with docetaxel, cisplatin, and 5-fluorouracil for esophageal cancer

Purpose

We aimed to evaluate the safety, tolerability, and efficacy of combination preoperative chemoradiotherapy as first-line treatment in patients with advanced esophageal cancer.

Methods

We performed a phase I dose-escalation trial of docetaxel at 25–40?mg/m² in four planned dose levels in 3–6 patient cohorts on days 1, 15, 29, and 43 administered in combination with cisplatin (70?mg/m² on days 1 and 29) and 5-fluorouracil (70?mg/m²/day on days 1–4 and 29–32) and concurrent radiation therapy (40?Gy). The tumors were resected during weeks 10–13.

Results

This study included 7 patients with esophageal cancer. The dose-limiting toxicity was observed at a biweekly docetaxel dose of 30?mg/m² when patients developed grade 3 febrile neutropenia, grade 4 thrombocytopenia, and grade 4 pain/esophagus, resulting in a maximum tolerated dose of 25?mg/m². Grade 3/4 hematological toxicity was observed in 71% of the patients and grade 3/4 non-hematological toxicity in 57%. The overall tumor response rate was 86% (complete, 57% and partial, 29%). All patients underwent surgery, and there were no deaths as a result of postoperative complications.

Conclusions

This preoperative chemoradiotherapy regimen using triplets is feasible but results in moderate toxicity. It is noteworthy that this regimen was associated with a high rate of pathological complete remission.     

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.     

A randomized phase II trial of two different 4-drug combinations in advanced pancreatic adenocarcinoma: cisplatin, capecitabine, gemcitabine plus either epirubicin or docetaxel (PEXG or PDXG regimen)

Purpose

PEFG regimen (P:cisplatin, E:epirubicin, F:5-fluorouracil, G:gemcitabine) significantly prolonged progression-free (PFS) and overall survival (OS) of patients with advanced pancreatic adenocarcinoma (PA) with respect to standard gemcitabine. The current trial was aimed at assessing whether the replacement of E with docetaxel (D) may improve 6?months PFS (PFS6).

Methods

Chemo-naive patients with stage III or metastatic PA received P (30?mg/m² day 1 and 15), G (800?mg/m² day 1 and 15), and capecitabine (1,250?mg/m²/day?days 1?C28, without a break) and were randomized to receive either D at 25?C30?mg/m² day 1 and 15 (arm A: PDXG regimen) or E at 30?mg/m² day 1 and 15 (arm B: PEXG regimen). Cycles were repeated every 28?days for a maximum of 6?months. The Fleming design was used to calculate the sample size on the probability of being PFS6. Assuming P0?=?40% and P1?=?60%, ???=?0.05 and ???=?0.10; the study was to enroll 52 patients per arm.

Results

Between July 2005 and September 2008, 105 patients were enrolled, stratified by stage and randomized. Patients?? characteristics were (A/B) the following: median age 61/59, PS?>70 92/88%, metastatic disease 66/65%. PFS6 was 58%, and median OS was 11?months in both arms. A partial response was observed in 60/37% of patients. Main per cycle G3-4 toxicity was the following: neutropenia 4/13%, thrombocytopenia 2/4%, anemia 4/4%, and fatigue 6/3%.

Conclusions

The inclusion of D instead of E yielded more objective response and less G3-4 neutropenia but did not improve PFS and OS. The present trial confirms the relevant impact on outcome of advanced PA of 4-drug regimens.