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Japanese Journal of Clinical Oncology Advance Access originally published online on March 4, 2009
Japanese Journal of Clinical Oncology 2009 39(4):237-243; doi:10.1093/jjco/hyp008
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© The Author (2009). Published by Oxford University Press. All rights reserved

Multi-center Phase II Trial of Weekly Paclitaxel Plus Cisplatin Combination Chemotherapy in Patients with Advanced Gastric and Gastro-esophageal Cancer

Qing Sun1, Chaoying Liu2, Haijun Zhong3, Baoliang Zhong4, Haiyuan Xu5, Wenxiang Shen5 and Daoyuan Wang6

1 Department of Medical Oncology, Wuxi 2nd Hospital, Nanjing Medical University
2 Department of Medical Oncology, Wuxi People Hospital, Nanjing Medical University, Nanjing
3 Department of Medical Oncology, Zhejiang Cancer Hospital, Zhejiang Traditional Chinese Medicine University, Zhejiang
4 School of Public Health, Peking University, Peking
5 Department of Medical Oncology, The First People of Kunshan Hospital, Medical School of Jiangsu University, Jiangsu
6 AmMed Cancer Center, Shanghai Ruijin Hospital, Medical School of Shanghai Jiaotong University, Shanghai, People's Republic of China

For reprints and all correspondence: Daoyuan Wang, AmMed Cancer Center, Shanghai Ruijin Hospital, Medical School of Shanghai Jiaotong University, No. 197, Rui Jin Er Lu, Shanghai 200025, People's Republic of China. E-mail: ghealth2008{at}gmail.com

Received November 21, 2008; accepted January 12, 2009


   Abstract
TOP
 Abstract
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Acknowledgements
 References
 
Objective: This study is performed to evaluate the response rate, time to progression and safety of the combination chemotherapy with weekly paclitaxel plus cisplatin in advanced gastric and gastro-esophageal cancer.

Methods: The paclitaxel 100 mg/m2 was administered through a 1 h intravenous infusion on Days 1 and 8. The cisplatin 30 mg/m2 was also administered along with a program of forced diuresis that included at least 2000 ml of fluids after the paclitaxel infusion over 30 min on Days 1 and 8. The chemotherapy was given every 21 days and continued until disease progression, patient refusal or an unacceptable toxicity up to nine cycles.

Results: Forty-seven (95.9%) of the 49 patients were assessable for response. Two cases of complete response and 19 cases of partial response were confirmed, giving an overall response rate of 42.9% (95% CI, 29.0–56.8%). The median time to progression and overall survival for all patients were 5.9 months (95% CI, 1.6–9.1 months) and 11.2 months (95% CI, 6.1–21.3 months). The most severe hematologic adverse event was neutropenia, which occurred with a Grade 3 intensity in 17.0% and Grade 4 in 4.3%. Grade 3 vomiting, peripheral neuropathy and elevated transaminase were observed in 4.3%, 4.3% and 2.1% of patients.

Conclusions: Combination of weekly paclitaxel plus cisplatin is an active regimen with excellent tolerability as a first-line treatment of advanced gastric and gastro-esophageal cancer.

Key Words: advanced gastric cancer • advanced gastro-esophageal cancer • paclitaxel • cisplatin • weekly


   INTRODUCTION
TOP
 Abstract
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Acknowledgements
 References
 
Although the incidence of gastric carcinoma has fallen in most Western countries, it remains a significant problem in terms of global health and is the second most common cause of cancer mortality worldwide (1). Gastric cancer is often diagnosed at a very advanced stage, with approximately half of all patients presenting with unresectable, locally advanced, or metastatic disease. Four randomized studies comparing best-supportive care with best-supportive care plus chemotherapy for advanced gastric cancer have shown that chemotherapy can improve survival and quality of life (2–5). 5-Fluorouracil (5-FU) and/or cisplatin (CDDP)-based combination chemotherapy continues to be widely used, but the continuing lack of progress of chemotherapy for the treatment of gastric cancer has prompted the evaluations of new agents and/or combinations including taxanes, irinotecan, capecitabine, S-1 and others.

Paclitaxel (TXL), derived from the bark of the Pacific yew, Taxus brevifolia, is one of the most active anticancer drugs for the treatment of solid tumors, effectively blocking cancer cells in the G2/M phase through the inhibition of microtubular depolymerization (6,7). An administration schedule at doses of 175–225 mg/m2 intravenous infusion every 3 weeks has been widely accepted (8). In addition, several Phase II studies have shown that paclitaxel, alone or in combination with cisplatin or 5-FU, is also active against advanced gastric cancer (9–12). However, a relatively high incidence of Grade III or IV neutropenia (14–35%) is one of the major adverse effects. Furthermore, recent clinical studies have demonstrated that weekly schedules of intravenous paclitaxel have promising antitumor activity with tolerable safety profiles for several types of solid tumors, including lung, breast and ovarian cancer (13–15). For example, Markman et al. (15) reported that weekly single agent paclitaxel achieved an objective response rate of 25% and only 1% of cycles were modified due to side effects in 53 patients with platinum/paclitaxel-refractory ovarian cancer. CDDP is an active chemotherapeutic agent against gastric cancer. Treatment regimens including CDDP have shown high response rates (16–18). CDDP has demonstrated synergism with a variety of cytotoxic drugs, and synergism between TXL and CDDP has been established and reported (19–20).

TXL and CDDP have different modes of action and fewer overlapping toxicities than other combinations. The most widely used TXL + CDDP regimen involves high-dose TXL (175–200 mg/m2) and CDDP (60–75 mg/m2) administered thrice-weekly. However, treatment is sometimes delayed by neurotoxicity and higher dose of CDDP is associated with higher neurotoxicity and more severe renal damage. Rosenberg et al. (21) performed a comparative study on TXL administration modalities in patients with ovarian cancer and reported that weekly administration of TXL is better than a thrice-weekly administration even though treatment effects are comparable, because the incidences of side effects are clearly lower for the weekly administration (particularly with respect to myelosuppression and peripheral neuropathy). In addition, Seidman et al. (14) conducted a Phase II clinical study in which TXL was administered weekly at 80–120 mg/m2 to patients with adriamycin-resistant breast cancer and reported a response rate of 53% with high tolerability. Moreover, the weekly application of TXL 80 mg/m2 as a 1 h infusion has been suggested to be associated with lower hematologic toxicity while capable of achieving a higher dose intensity than TXL administration at 175 mg/m2 thrice-weekly (22). These results show that the divided administration of TXL may reduce myelosuppression and neurotoxicity.

Based on these results, we conducted a multi-center Phase II trial of combination chemotherapy with weekly paclitaxel plus cisplatin to evaluate the response rate, time to progression (TTP) and safety of this regimen in advanced gastric and gastro-esophageal cancer.


   PATIENTS AND METHODS
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 Acknowledgements
 References
 
Eligibility Criteria
All the patients involved in the current study had histologically confirmed metastatic or recurrent gastric adenocarcinoma with at least one unidimensionally measurable lesion (i.e. a diameter of ≥1 cm, as assessed by spiral computed tomography). The patients were 18–75 years of age with a performance status of 0–2 on the Eastern Cooperative Oncology Group (ECOG) scale. Plus, adequate hematological (absolute neutrophil count ≥1.5 x 109/l, platelet count ≥100 x 109/l, hemoglobin ≥9 g/dl), renal (serum creatinine ≤1.5 mg/dl and creatinine clearance ≥50 ml/min) and hepatic (total bilirubin ≤2.0 mg/dl and serum transaminase level ≤3 times the upper limit of the normal range) levels were also required. Patients who had received adjuvant chemotherapy completed 4 weeks before entry were eligible. Patients were ineligible if they had previously received palliative chemotherapy or radiation therapy, or had other severe medical illnesses, CNS metastasis, another active malignancy or history of anaphylaxis to drugs. The Institutional Review Board of each author’s institution approved the protocol, and written informed consent was obtained from all patients before enrollment.

Study Treatment
The paclitaxel (Fuwang®; Yangtze River Pharm Co., Ltd, Jiangsu Province, People's Republic of China) 100 mg/m2 was administered through a 1 h intravenous infusion on Days 1 and 8. The cisplatin 30 mg/m2 was also administered along with a program of forced diuresis that included at least 2000 ml of fluids after the paclitaxel infusion over 30 min on Days 1 and 8. The chemotherapy was given every 21 days and continued until disease progression, patient refusal or an unacceptable toxicity up to nine cycles. As prophylactic agents, dexamethasone (iv, 20 mg), diphenhydramine (po, 50 mg) and ranitidine hydrochloride (iv, 50 mg) were given 30 min before paclitaxel administration. All patients received adequate antiemetic therapy prior to chemotherapy. Granulocyte colony-stimulating factor was administered at physician’s discretion or taking insurance status of the countries in considerations. Antiemetic treatment was routinely given before each cycle of chemotherapy.

Dose Modification
The next course of treatment was only begun when the neutrophil count was ≥1.5 x 109/l, platelet count ≥100 x 109/l and any other treatment-related toxicities were less than or equal to Grade 1; otherwise, treatment was withheld for up to 2 weeks. If adverse events did not improve to Grade 0 or 1 after 2 weeks, the patients were excluded from the study.

Treatment was continued at the same dose if patients experienced Grade 1 toxicities or other toxicities considered by the investigator unlikely to become serious or life-threatening (e.g. alopecia). For all other treatment-related adverse events with a Grade 2 intensity or higher, the dose modification scheme described below was implemented. The paclitaxel and cisplatin treatment on Day 8 was omitted in the presence of a Grade ≥3 hematological or non-hematological toxicity, and the patient then reevaluated weekly until regressing to less than or equal to Grade 1. Missed doses of paclitaxel and cisplatin were not made up. The subsequent cycle of treatment was reduced by 20% doses of paclitaxel and cisplatin in the case of a repeated Grade 2 or any Grade 3 toxicity, and reduced by 40% in the case of a repeated Grade 3 or any Grade 4 toxicity during the preceding cycle. If a dose reduction of >40% was required, the patients were excluded from the study.

Response to Treatment and Adverse Effects
Before entering the study, all patients received physical examination, and full blood count and serum chemistry analyses. Chest X-ray, ECG, upper gastrointestinal endoscopies, abdominal computer tomographic scans and other appropriate procedures were also performed. Patients were given a physical examination, a subjective/objective symptom evaluation and routine blood tests twice-weekly. Every 4 weeks, a biochemistry blood examination was added to this basal evaluation. After every two cycles of treatment, response was evaluated by two independent experts using RECIST criteria. Of the lesions observed prior to treatment, a maximum of 5 measurable lesions from each metastasized organ up to a total of 10 lesions were selected as target lesions. In cases of partial or complete response, a confirmative computer tomographic (CT) scan was performed 4 weeks later and this was followed by a CT scan after every two treatment cycles. Toxicity was reported using a National Cancer Institute-Common Toxicity Criteria (NCI-CTC) version 2.0 toxicity scale.

Statistical Analysis
The current trial used a two-stage optimal design, as proposed by Simon, with an 80% power to accept the hypothesis and 5% significance to reject the hypothesis (23). Plus, the current trial was designed to detect a response rate of 40% when compared with a minimal, clinically meaningful response rate of 20%. Allowing for a follow-up loss rate of 10%, the total sample size was 48 patients with a measurable disease. All enrolled patients were included in the intention-to-treat analysis of efficacy. The duration of response, time to progression (TTP) and survival analyses were all estimated using the Kaplan–Meier method. The duration of response was defined as the interval from the onset of a complete response (CR) or partial response (PR) until evidence of disease progression was found. Meanwhile, the TTP was calculated from the initiation of chemotherapy to the date of disease progression, whereas overall survival was measured from the initiation of chemotherapy to the date of the last follow-up or death. The statistical data were obtained using an SPSS software package (SPSS 11.5 Inc., Chicago, IL, USA).


   RESULTS
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 Acknowledgements
 References
 
Patient Characteristics
From June 2005 to July 2006, a total of 49 patients were enrolled in the current study from five centers. The characteristics of the patients are summarized in Table 1. The median age was 54 (range, 21–74) years, with 34 males and 15 females. Most of the patients (93.9%) had a good performance status (ECOG 0 or 1). Thirty-two (65.3%) patients had a metastatic disease, whereas 17 patients had a recurrent disease after surgical resection (total or subtotal gastrectomy) of the primary tumor. Distal lymph nodes, peritoneum and the liver were the most common sites of the metastases. No patients had received prior chemotherapy or radiotherapy.


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  		Table 1. Patient characteristics

 
Efficacy and Survival
Forty-seven (95.9%) of the 49 patients were assessable for response, of the two patients not assessable, one was lost to follow-up after the first cycle of the treatment and another died after the first cycle of unknown cause, although brain metastasis was suspected. All efficacy data are reported using the intent-to-treat patient population (Table 2). Two cases of CR and 19 cases of PR were confirmed, giving an overall response rate of 42.9% (95% CI, 29.0–56.8%). Of 21 responses, 14 (66.7%) were observed after four cycles, 4 (19.0%) after six cycles and 3 (14.3%) after eight cycles of chemotherapy. The median follow-up period was 12.1 months. The median TTP for all patients was 5.9 months (95% CI, 1.6–9.1 months) (Fig. 1). The estimated median overall survival was 11.2 months (95% CI, 6.1–21.3 months) (Fig. 1). The estimate of overall survival at 12 months was 40.4% (95% CI, 26.4–54.5%).


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  		Table 2. Tumor response (intention-to-treat analysis)

 

Figure 1
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  		Figure 1. Time to disease progression and overall survival for intention-to-treat population (n = 49).

 
Post-study Treatment
After disease progression, 26 patients (53.1%) received second-line chemotherapy: 16 patients received oxaliplatin/leucovirin/5-FU (FOLFOX); 6 patients received irinotecan/leucovirin/5-FU (FOLFIRI); and 4 patients received capecitabine (±cisplatin). Two patients (7.7%) achieved PR and 4 (15.4%) had stable disease in response to second-line chemotherapy, the median TTP was 1.7 months (95% CI = 1.4–2.0 months). Four patients (8.2%) received palliative radiotherapy, and one patient underwent total gastrectomy due to cancer bleeding.

Toxicity
A total of 145 cycles were administered in 47 patients assessable for toxicity, with a median of 4 cycles per patient (range 1–8 cycles). The occurrence and the incidence of the hematologic and non-hematologic toxicities are shown in Table 3. The most severe hematologic adverse event was neutropenia, which occurred with Grade 3 intensity in 8 (17.0%) patients and Grade 4 in 2 (4.3%) patients. Thrombocytopenia occurred with Grade 3 intensity in 1 (2.1%) patient. However, no Grade 4 thrombocytopenia was observed. Anorexia, nausea/vomiting and alopecia were the most common non-hematological toxicities. Grade 1/2 anorexia, nausea, vomiting and alopecia were observed in 26 (55.3%), 9 (19.1%), 8 (17.0%) and 17 (36.2%) patients. And Grade 3 vomiting, peripheral neuropathy and elevated transaminase were observed in 2 (4.3%), 2 (4.3%) and 1 (2.1%) patients. Yet, no Grade 4 non-hematologic toxicity was observed. Six patients (12.2%) were hospitalized due to treatment toxicities (five due to infections and one due to general weakness); however, there were no treatment-related deaths during this study. Overall, 5 (10.2%) patients required a dose reduction of paclitaxel on Day 1, while dose omissions of paclitaxel on Day 8 were needed in 11 (7.6%) cycles. Also, a total of 21 (14.5%) cycles were delayed. The most common reasons for the dose modification of paclitaxel were neutropenia (4 patients, 11 cycles) and nausea (2 patients, 2 cycles). The mean dose intensity for the paclitaxel and cisplatin over all treatment cycles was 60.78 and 21.21 mg/m2/week, corresponding to 91.1% and 91.0% of the planned dose intensities, respectively.


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  		Table 3. Toxicities of paclitaxel plus cisplatin combination chemotherapy (by patients)

 

   DISCUSSION
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
Acknowledgements
 References
 
In advanced gastric cancer, systemic chemotherapy has been tried as a palliative purpose, leading to improvement of tumor responses, quality of life and survival compared with best supportive care (2–5). However, the standard chemotherapy has not yet been established. The continuing lack of substantial progress in the treatment of advanced gastric cancer, particularly in patients with poor performance status or compromised organ function, who are unlikely to tolerate potentially active but toxic regimens, has prompted investigators to evaluate new agents and/or drug combinations including docetaxel, paclitaxel and irinotecan (10,11,17,24,25).

The aim of this study was to assess the efficacy and toxicity of weekly TXL + CDDP combination treatment. Since the response rate for TXL was determined to be 23% during its development, the threshold efficacy rate was set at 20% for combination chemotherapy in this study. In addition, the expected efficacy rate for the combination chemotherapy was set at approximately 40%. This study confirms that the weekly TXL + CDDP have favorable patterns of toxicity; we have proven the expected efficacy rate of TXL + CDDP in this study. Its clinical objective response rate was 42.9% (95% CI, 29.0–56.8%). The median TTP and overall survival for all patients were 5.9 months (95% CI, 1.6–9.1 months) and 11.2 months (95% CI, 6.1–21.3 months). TXL and CDDP have different modes of action and fewer overlapping toxicities than other combinations. The most widely used TXL + CDDP regimen involves high-dose TXL (175–200 mg/m2) and CDDP (60–75 mg/m2) administered thrice-weekly (12,26,27). However, treatment is sometimes delayed by neurotoxicity and higher dose of CDDP is associated with higher neurotoxicity and more severe renal damage. Lee et al. (28) performed a Phase II trial of low-dose paclitaxel (145 mg/m2) and cisplatin (60 mg/m2) in patients with advanced gastric cancer, and found the regimen of low-dose paclitaxel and cisplatin was active and well-tolerated in gastric cancer patients. Rosenberg et al. (21) performed a comparative study on TXL administration modalities in patients with ovarian cancer and reported that weekly administration of TXL is better than a thrice-weekly administration even though treatment effects are comparable, because the incidences of side effects are clearly lower for the weekly administration (particularly with respect to myelosuppression and peripheral neuropathy). In addition, Seidman et al. (14) conducted a Phase II clinical study in which TXL was administered weekly at 80–120 mg/m2 to patients with adriamycin-resistant breast cancer and reported a response rate of 53% with high tolerability. Moreover, the weekly application of TXL 80 mg/m2 as a 1 h infusion has been suggested to be associated with lower hematologic toxicity while capable of achieving a higher dose intensity than TXL administration at 175 mg/m2 thrice-weekly. Four Phase II studies using bi-weekly TXL + CDDP have been conducted and both reported a high response rate in esophageal cancer (bi-weekly administrations of TXL 180 mg/m2 + CDDP 30 mg/m2) (29) and in gastric cancer (bi-weekly administration of TXL 160 mg/m2 + CDDP 60 mg/m2) (30) and (bi-weekly administration of TXL 140 mg/m2 + CDDP 30 mg/m2) (31,32). The details were listed in Table 4. These results show that the divided administration of TXL may reduce myelosuppression and neurotoxicity.


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  		Table 4. Phase II trial of paclitaxel ± cisplatin chemotherapy in patients with advanced gastric cancer, or esophagus cancer

 
Here, we conducted a multi-institutional cooperative Phase II study of a weekly regimen (weekly administration of TXL 100 mg/m2 + CDDP 30 mg/m2), to assess the efficacy and toxicity of this regimen. The main toxicity of this regimen used in the present study was neutropenia. Hematologic toxicities consisted of neutropenia Grade 3 in 17.0% and Grade 4 in 4.3%, which is substantially lower than the previous reports (12,29–33). Although the incidence of neutropenia in this study was found to be similar with higher dose TXL and CDDP regimen (26), or higher than previous reports of advanced gastric cancer (27,28) (Table 4). In the current study, the combination chemotherapy of weekly paclitaxel and cisplatin, which can be administered on an outpatient basis, produced active antitumor activity and a safe toxicity profile in patients with advanced gastric and gastro-esophageal cancer.

We conclude that the combination of weekly paclitaxel plus cisplatin is an active regimen with excellent tolerability as a first-line treatment of advanced gastric and gastro-esophageal cancer. Although it was an active regimen with excellent tolerability, further trials are needed to determine whether it can be achieved in elderly patients or those in poor condition.


   Acknowledgements
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Acknowledgements
References
 
The authors are grateful to all the staff at the study centers who contributed to this study.

Conflict of interest statement

None declared.


   References
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Acknowledgements
 References
 
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3 Pyrhönen S, Kuitunen T, Nyandoto P, Kouri M. Randomised comparison of fluorouracil, epidoxorubicin and methotrexate (FEMTX) plus supportive care with supportive care alone in patients with non-resectable gastric cancer. Br J Cancer (1995) 71:587–91.[Web of Science][Medline]

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8 Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, et al. Eastern Cooperative Oncology Group. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med (2002) 346:92–8.[Abstract/Free Full Text]

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10 Bokemeyer C, Lampe CS, Clemens MR, Hartmann JT, Quietzsch D, Forkmann L, et al. A phase II trial of paclitaxel and weekly 24 h infusion of 5-fluorouracil/folinic acid in patients with advanced gastric cancer. Anticancer Drugs (1997) 8:396–9.[CrossRef][Medline]

11 Kollmannsberger C, Quietzsch D, Haag C, Lingenfelser T, Schroeder M, Hartmann JT, et al. A phase II study of paclitaxel, weekly, 24-hour continuous infusion 5-fluorouracil, folinic acid and cisplatin in patients with advanced gastric cancer. Br J Cancer (2000) 83:458–62.[CrossRef][Web of Science][Medline]

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13 Akerley W, Herndon JE, Egorin MJ, Lyss AP, Kindler HL, Savarese DM, et al. Weekly, high-dose paclitaxel in advanced lung carcinoma: a phase II study with pharmacokinetics by the Cancer and Leukemia Group B. Cancer (2003) 97:2480–6.[CrossRef][Web of Science][Medline]

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21 Rosenberg P, Andersson H, Boman K, Ridderheim M, Sorbe B, Puistola U, et al. Randomized trial of single agent paclitaxel given weekly versus every three weeks and with peroral versus intravenous steroid premedication to patients with ovarian cancer previously treated with platinum. Acta Oncol (2002) 41:418–24.[CrossRef][Web of Science][Medline]

22 Fennelly D, Aghajanian C, Shapiro F, O’Flaherty C, McKenzie M, O’Connor C, et al. Phase I and pharmacologic study of paclitaxel administered weekly in patients with relapsed ovarian cancer. J Clin Oncol (1997) 15:187–92.[Abstract/Free Full Text]

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24 Murad AM, Petroianu A, Guimaraes RC, Aragao BC, Cabral LO, Scalabu A, et al. Phase II trial of the combination of paclitaxel and 5-fluorouracil in the treatment of advanced gastric cancer: a novel, safe, and effective regimen. Am J Clin Oncol (1999) 22:580–6.[CrossRef][Web of Science][Medline]

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26 Park SR, Oh DY, Kim DW, Kim TY, Heo DS, Bang YJ, et al. A multi-center, late phase II clinical trial of Genexol (paclitaxel) and cisplatin for patients with advanced gastric cancer. Oncol Rep (2004) 12:1059–64.[Web of Science][Medline]

27 Seo BG, Oh SY, Lee DM, Yoo HS, Lee S, Kim SG, et al. A phase II study of paclitaxel and cisplatin as salvage therapy for patients with advanced or metastatic gastric cancer. Cancer Res Treat (2007) 39:6–9.

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33 Kim JG, Sohn SK, Song HS, Kwon KY, Do YR, Lee KH, et al. Multicenter phase II study of weekly paclitaxel plus cisplatin combination chemotherapy in patients with advanced gastric cancer. Cancer Chemother Pharmacol (2007) 60:863–9.[CrossRef][Web of Science][Medline]


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