Japanese Journal of Clinical Oncology Advance Access originally published online on May 10, 2005
Japanese Journal of Clinical Oncology 2005 35(5):251-255; doi:10.1093/jjco/hyi077
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© 2005 Foundation for Promotion of Cancer Research
Phase II Study of Paclitaxel and Carboplatin in Advanced Gastric Cancer Previously Treated with 5-Fluorouracil and Platinum
1 Division of Oncology, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine and 2 Department of Internal Medicine, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Korea
For reprints and all correspondence: Heung Moon Chang, Division of Oncology, Department of Internal Medicine, Asan Medical Center, 388-1 Pungnap-dong, Songpa-gu, Seoul 138-736, Korea. E-mail: changhm{at}amc.seoul.kr
Received March 31, 2005; accepted April 1, 2005
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Abstract |
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 TOP Abstract INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Background: The combination of paclitaxel and carboplatin has been used to treat patients with many types of tumor, including gastric cancer. We evaluated the efficacy and safety of this combination in advanced gastric cancer patients previously treated with 5-fluorouracil and platinum.
Methods: Patients who had pathologically been proven to have measurable lesions were treated with paclitaxel (200 mg/m2 for 3 h) and carboplatin [area under the concentration–time curve (AUC = 6)] on day 1 and in 21 day cycles.
Results: A partial response was achieved in 10 of 45 patients [22%, 95% confidence interval (CI), 10–34]. Of the 32 patients previously treated with cisplatin, four (13%) achieved partial response, whereas, of the 13 patients previously treated with heptaplatin, six (46%) achieved partial response. In all patients, the median time to progression was 14 weeks (95% CI, 10–18), and the median overall survival was 32 weeks (95% CI, 26–38). The most common grade 3/4 adverse events were neutropenia (40% of patients) and neuropathy (2.2%). Two patients developed neutropenic fever. However, there were no treatment-related deaths.
Conclusions: Combination chemotherapy with paclitaxel and carboplatin is feasible in patients with advanced gastric cancer who were previously treated with 5-fluorouracil and platinum.
Key Words: gastric cancer • carboplatin • paclitaxel
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INTRODUCTION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Although the incidence of advanced gastric cancer (AGC) is decreasing in many countries, it is still one of the most prevalent malignancies in many countries including Korea (1,2). Recently, improvements in early diagnosis have increased the number of patients who are able to undergo curative resection. However, tumor recurrence is frequently observed and many patients have metastatic lesions at the time of initial diagnosis. Patients with unresectable locally advanced or metastatic lesions have been treated with systemic chemotherapy, and several randomized studies have demonstrated the benefit of chemotherapy compared with best supportive care (3–5).
Cisplatin (CDDP) is one of the most commonly used chemotherapeutic agents in AGC. It has been used combined with other drugs such as 5-fluorouracil (5-FU), doxorubicin or etoposide. Heptaplatin (SKI 2053R, Sunpla®, SK Pharma, Seoul, Korea) is a new platinum derivative which was developed in Korea and showed a response rate of 17.1% as a single agent and 29.7% in combination with 5-FU in AGC (6–8). However, when these platinum-based chemotherapies have failed, there is no effective salvage regimen in AGC.
Paclitaxel is an anticancer agent that promotes the formation of tubulin dimers and stabilizes microtubules against depolymerization (9). This drug has a broad spectrum of antitumor activity and moderate toxicity profiles. When used as a single agent to treat previously untreated AGC, paclitaxel induced a response in 17% of patients (10). Moreover, when used in combination with 5-FU and/or cisplatin, it showed response rates of 50–65.6% (11,12).
Carboplatin is a cisplatin analog introduced into clinical use in 1981 to circumvent some of the toxicities of cisplatin. Because of its favorable toxicity profiles, carboplatin has replaced cisplatin in several cancers, including ovarian and lung cancers. Paclitaxel and carboplatin have different mechanisms of action and non-cross-toxicities. For this reason, the combination of these two drugs is widely used to treat many types of tumor, including non-small cell lung, ovarian, esophageal, and head and neck cancers. In AGC patients, first-line therapy with the combination of paclitaxel and carboplatin has shown response rates of 29.4–33% (13,14). In this study, we evaluated the efficacy and toxicity of the combination chemotherapy with paclitaxel and carboplatin in patients with AGC who had been previously treated with 5-FU and platinum.
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PATIENTS AND METHODS |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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PATIENT ELIGIBILITY
Eligiblily criteria were: histologically proven unresectable gastric adenocarcinoma that progressed or recurred after treatment with 5-FU plus platinum agents, cisplatin or heptaplatin, used in an adjuvant setting or to treat metastatic disease. Each patient was required to have at least one measurable target lesion with at least one diameter
2 cm on computed tomographic (CT) scan, or 1 cm as determined by physical examination. Ages had to be within the range of 18–70 years and each patient had to have an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or better with adequate hematological [white blood cell count >4 x 109/l, absolute neutrophil count (ANC) >1.5 x 109/l and platelet count >100 x 109/l], renal (serum creatinine level <1.5 mg/dl) and hepatic function (serum bilirubin level <1.5 mg/dl, transaminase levels <3 times normal, or <5 times normal for patients with liver metastases). Patients had to receive no chemotherapy treatment for at least 4 weeks, and no radiation therapy for at least 3 weeks, prior to enrollment. Patients were ineligible if they had been previously exposed to taxanes or carboplatin or had co-existing malignant diseases at other sites, symptomatic central nervous system metastases, or other diseases for which systemic chemotherapy was contraindicated. The protocol was approved by the ethics and human investigation committee of the institute. Written informed consent was obtained from each patient before entry into the study.
TREATMENT SCHEDULE
The chemotherapy regimen consisted of paclitaxel and carboplatin. Carboplatin dose was calculated according to the Calvert formula, using an estimate of creatinine clearance to predict an area under the concentration–time curve (AUC) of 6.0. On day 1, dexamethasone (20 mg), diphenhydramine (50 mg) and ranitidine (50 mg) were administered intravenously (i.v.) 30 min prior to paclitaxel administration to prevent hypersensitivity. Each patient was subsequently administered paclitaxel (200 mg/m2) as a 3 h i.v. infusion followed by the calculated dose of carboplatin. These chemotherapy treatments were repeated every 21 days.
Dose modifications were based on hematological and non-hematological toxicities. Dose reduction of one level, to paclitaxel 175 mg/m2 and carboplatin AUC 5.0, was indicated for neutropenic fever, ANC 
0.5 x 109/l for 5 days, or grade 4 thrombocytopenia during the previous cycle. Further dose reduction, of two levels, to paclitaxel 150 mg/m2 and carboplatin AUC 4.0, was indicated for recurrent neutropenic fever, ANC 0.5 x 109/l or grade 4 thrombocytopenia after the first dose reduction. If neutropenia or thrombocytopenia was grade 1 on the day of treatment, the dose was reduced by one. If neutropenia or thrombocytopenia was grade 2 on the day of treatment, chemotherapy was withheld until the patient had recovered completely or to grade 1. Paclitaxel was reduced by one level in patients experiencing grade 2 neuropathy or grade 3 or 4 arthralgia/myalgia, and it was decreased by two levels for patients experiencing grade 3 neuropathy. If a patient had any other grade 3 or 4 toxicity on day 1 of the next planned cycle, with the exception of alopecia, nausea or vomiting, or anemia, chemotherapy was withheld for a minimum of 1 week until the patient had improved to grade 1, at which time chemotherapy was re-instituted. If the toxicity did not improve to grade 1 after 3 weeks, the patient was removed from the study.
FOLLOW-UP EVALUATION
Before study entry, for each patient a detailed medical history was taken and they underwent a complete physical examination, at which time that patient's weight, height and ECOG performance status were recorded. Pre-treatment examination included complete blood cell count (CBC), serum chemistry panel, electrocardiogram and chest radiography. Abdomen–pelvic CT was performed to document and measure tumor lesions. Physical examination, assessment of performance status, CBC and chemistry were determined at the start of each further treatment cycle, with chest X-ray and abdomen–pelvic CT repeated every two cycles. Responses were classified according to the World Health Organization criteria. Treatment toxicities were evaluated according to the National Cancer Institute Common Toxicity Criteria version 1.0.
STATISTICAL ANALYSIS
The primary end-point was response to treatment. The secondary end-points were time to progression (TTP), defined as the time from the day of initiation of chemotherapy to the date of progression of disease, and overall survival (OS), defined as the time from the day of initiation of chemotherapy to the date of last follow-up evaluation or death.
This trial utilized a two-stage testing design (15). Assuming a true response rate of at least 20%, 14 patients would be recruited initially. If no responses were observed, the trial would be closed because, if the true response rate were at least 20%, the probability of obtaining no responses in 14 patients would be <0.05. It was planned to recruit a total of 43 patients, if at least one response would be observed in the first stage. Survival probabilities were estimated by the Kaplan–Meier method. The SPSS program for Windows (Release 10.0.1) was used for analysis.
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RESULTS |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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PATIENT CHARACTERISTICS
Between November 1996 and May 2001, 45 patients (34 males and 11 females; median age 52 years) were enrolled in this study (Table 1). Of the 45 patients, 32 had been treated previously with 5-FU plus cisplatin, whereas the other 13 had been treated with 5-FU plus heptaplatin. At the time of enrollment, disease status was as follows: nine patients had a recurrence at least 6 months after the end of adjuvant chemotherapy, four patients had a recurrence within 6 months from the end of adjuvant chemotherapy, and 32 patients had progressed after first-line chemotherapy for metastatic disease.
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RESPONSE AND SURVIVAL
A total of 139 chemotherapy cycles were administered to these 45 patients, and the median number of delivered cycles was two (range 1–7). Partial response (PR) was achieved in 10 patients [22%; 95% confidence interval (CI) 10–34], stable disease in 20 patients (44%) and disease progression in 15 patients (33%). Three of the nine patients who had experienced a recurrence at least 6 months after the end of adjuvant chemotherapy showed a PR (33%) and seven of the 32 patients who had progressed after first-line chemotherapy achieved a PR (22%). There was no response in four patients who had a recurrence within 6 months from the end of adjuvant chemotherapy. Of the eight patients who had responded to prior first-line chemotherapy, one patient (13%) achieved a PR and six (25%) of 24 patients who had no response to first-line chemotherapy had responded. Of the 32 patients who had been previously treated with cisplatin, four (13%) achieved a PR, whereas, of the 13 patients previously treated with heptaplatin, six (46%) achieved a PR. The difference in response rate was statistically significant (P = 0.01).
For all 45 patients, the median TTP was 14 weeks (95% CI 10–18); in responders, however, the median TTP was 17 weeks (95% CI 3–31). Median OS of all patients was 32 weeks (95% CI 26–38) and median OS of responders was 40 weeks (95% CI 29–50) (Fig. 1). The median OS of the patients who had relapsed at least 6 months after the end of adjuvant chemotherapy and had a recurrence within 6 months was 50 and 25 weeks, respectively. The median OS of the patients who had progressed after first-line chemotherapy was 32 weeks.
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TOXICITY
Toxicity was evaluated in all 45 patients (Table 2). Hematological toxicities included grade 3 neutropenia in nine patients (20.0%), grade 4 neutropenia in nine patients (20.0%) and grade 3 thrombocytopenia in two patients (4.4%). The most common non-hematological toxicities were neuropathy and arthralgia. Use of dexamethasone, diphenhydramine and ranitidine as pre-medication resulted in the absence of any hypersensitivity reactions. Also, there was no renal toxicity. Two patients developed neutropenic fever, but there was no treatment-related death.
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Currently, there is no standard salvage regimen for patients with AGC who progress after first-line chemotherapy. Several regimens have been evaluated as second-line treatment, and their response rates ranged from 0 to 30%, with survival times ranging from 3 to 8 months (16–18). These regimens are regarded as ineffective, prompting major efforts to evaluate new drugs. Paclitaxel is a representative of such a new drug because it has different cytotoxic mechanisms from the older chemotherapeutic agents, such as cisplatin and 5-FU, against gastric cancer cell lines (19). In AGC patients, paclitaxel treatment obtained a response rate of 17% (10). Although few studies have evaluated the efficacy of paclitaxel as a second-line treatment in patients with AGC, it has been shown that, in patients with gastric carcinoma refractory to prior chemotherapy, paclitaxel alone attained response rates of 20–22.2% (20,21).
We observed that the combination of paclitaxel (200 mg/m2) and carboplatin (AUC 6) gave a response rate of 22%. This can be compared with a response rate of 27.7% in previously treated AGC patients administered slightly lower doses of paclitaxel (175 mg/m2) and carboplatin (AUC 5) (22). The response rate of 22% observed here was equal to that of paclitaxel alone, suggesting that the addition of carboplatin had no effect on the response rate. This may be due to the patients' prior chemotherapy regimens, all of which included platinum-based agents. This is supported by our finding that patients who had been treated previously with cisplatin showed a lower response rate (13%) than those treated with heptaplatin (46%). Cross-resistance of cell lines to cisplatin and carboplatin has been observed in vitro, and there is evidence of partial cross-resistance in vivo as well. In contrast, cross-resistance between heptaplatin and cisplatin appears to be lower in experimental models, with heptaplatin having antitumor activity against cisplatin-resistant cell lines (6). These findings suggest that the response rate to salvage therapy with paclitaxel and carboplatin might be higher in patients not previously exposed to cisplatin.
It is also possible that carboplatin itself may have no effect on gastric cancer. This agent, however, has shown antitumor activity against gastric cancer cell lines and in animal models of gastric cancer (23). In addition, carboplatin has shown marginal activity in patients with stomach cancer, with response rates of 6–10% as a single agent (24,25). Synergistic interactions between paclitaxel and platinum compounds have been demonstrated in various cell lines, and combination chemotherapy with paclitaxel and carboplatin has shown considerable antitumor activities in many human cancers, including ovarian, non-small cell lung, and head and neck cancers (26). These findings suggest that the minimal effect of adding carboplatin to paclitaxel in our study may not be caused by the low efficacy of carboplatin against gastric cancer. Rather, we regard it more likely to be due to the previous exposure of these patients to cisplatin and the cross-resistance of cisplatin and carboplatin.
Tolerability is one of the most important considerations in the administration of second-line chemotherapy. The combination of paclitaxel and carboplatin, which is widely used in many cancers, is generally well tolerated. We also found that this combination was well tolerated even in our previously treated patients. Although we observed grade 3–4 neutropenia in 40% and grade 3 thrombocytopenia in 4.4% of patients, these toxicities were transient, and all patients recovered fully from them. Moreover, there was no treatment-related death.
In conclusion, combination chemotherapy with paclitaxel and carboplatin is feasible in patients with AGC who were previously treated with 5-FU and platinum.
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References |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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