Japanese Journal of Clinical Oncology Advance Access originally published online on January 17, 2006
Japanese Journal of Clinical Oncology 2006 36(2):104-108; doi:10.1093/jjco/hyi220
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© 2006 Foundation for Promotion of Cancer Research
Biweekly Paclitaxel and Gemcitabine for Patients with Advanced Urothelial Cancer Ineligible for Cisplatin-Based Regimen
Department of Urology, Kyoto University Graduate School of Medicine, Kyoto, Japan
For reprints and all correspondence: Osamu Ogawa, 54 Shogoin Kawaharacho, Sakyoku, Kyoto 606-8507, Japan. E-mail: ogawao{at}kuhp.kyoto-u.ac.jp
Received October 16, 2005; accepted November 30, 2005
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Abstract |
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 TOP Abstract INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Background: To avoid cisplatin-related gastrointestinal, renal and other toxicity while maintaining efficacy in the palliative setting or second line chemotherapeutic regimen for cisplatin-resistant urothelial cancer, chemotherapeutic regimens have been investigated that do not include cisplatin. The current study was designed to evaluate efficacy, clinical feasibility and safety of gemcitabine and paclitaxel (GP) regimen in patients with metastatic urothelial cancer who were ineligible for standard cisplatin-based combination chemotherapy.
Methods: Gemcitabine 2500 mg/m2 and paclitaxel 150 mg/m2 were administered intravenously every 2 weeks for 23 patients (17 males and 6 females) with advanced urothelial cancer who were ineligible for cisplatin-based chemotherapy; metastatic disease being resistant to cisplatin-based chemotherapy regimen in 14, heavy toxicity in prior cisplatin-based chemotherapy in three, poor ECOG performance in two and impaired renal function in four. Average age was 67 (53–77). Performance status was 0 in 18 patients, 1 in three patients and 2 in two patients.
Results: The overall response rate was 30% (95% CI 15.6–50.8%). Of the 23 patients, no patient attained CR and 7 patients had PR. In the cisplatin-resistant group, the response rate was 14.2% (2/14; 95% CI 4.0–39.9%). In the remaining patients ineligible for cisplatin, the response rate was 55.5% (5/9; 95% CI 26.6–81.1%). The median duration of response was 4 months (range 3–8). The median duration of survival for all patients was 12.1 months (95% CI 8.6–15.5). Myelosuppression, predominantly neutropenia, was the most common serious toxicity and toxicity of Grade 3 or greater was observed in six patients (26%). Among non-hematological toxicity, neuralgia was the most commonly observed and occurred in nine patients (39%) although no patient had toxicity of Grade 3 or greater. Three patients had interstitial pneumonitis possibly attributed to gemcitabine. One patient developed severe bilateral disease after two cycles of the regimen, which was partially resolved with corticosteroid therapy.
Conclusion: GP regimen is effective in some patients with cisplatin-resistant urothelial cancer and promising as second line chemotherapy. GP regimen is more effective and well tolerated as first line chemotherapy in patients ineligible for cisplatin-based chemotherapy. Toxicity is generally mild but care must be taken for patients with risk of interstitial pneumonitis. A further larger scale study is required to confirm the efficacy of the GP regimen.
Key Words: chemotherapy • gemcitabine • paclitaxel • urothelial cancer
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INTRODUCTION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin) has been the most common treatment regimen for advanced urothelial cancer (transitional cell carcinoma) since 1980s. Because of heavy toxicities and short response duration of M-VAC, safer and more effective regimens have been sought (1).
Recently, new agents emerged which have been shown effective against urothelial cancer such as gemcitabine, taxans, ifosfamide or irinotechan. New regimens for advanced urothelial cancer combining these new agents with cisplatin were thus investigated (1) and promising results have been accumulated in phase II trials. For example, in the phase II trial of paclitaxel, gemcitabine and cisplatin, reported response rate was 78% (2). Von der Masse et al. (3) conducted phase III randomized trial comparing M-VAC and GC (gemcitabine plus cisplatin) regimen, where GC was shown to have similar effect and less toxicity compared with M-VAC. These new regimens have a potential to be a new standard of combination chemotherapy for advanced urothelial cancer.
On the other hand, to avoid cisplatin-related gastrointestinal, renal and other toxicities while maintaining an efficacy in the palliative setting or as a second line chemotherapeutic regimen for cisplatin-resistant cancer, chemotherapeutic regiments were investigated that do not include cisplatin in urothelial cancer. It was shown that gemcitabin and paclitaxel (GP) regimen was effective in the treatment of patients with advanced urothelial cancer (4). Rothenberg et al. conducted a dose-setting trial of this regimen and showed that up to 3000 mg of gemcitabine could be administered safely (5). Sternberg et al. (6) reported a high response rate (60%) by biweekly administration of GP regimen in patients with cisplatin-resistant advanced urothelial cancer.
In this study, we evaluated the feasibility, toxicity and efficacy of the GP regimen in patients with metastatic urothelial cancer who were ineligible for standard cisplatin-based combination chemotherapy.
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PATIENTS AND METHODS |
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PATIENT CHARACTERISTICS
This study included 23 patients with histologically proven urothelial cancer and metastatic disease who were ineligible for standard cisplatin-based regimen (M-VAC) for some reason such as cisplatin-resistant tumors, severe toxicities in prior cisplatin-based chemotherapy, impaired renal function (serum creatinine level >2 mg/ml and/or creatinine clearance <30 ml/min) or poor ECOG performance status (2 or greater) between the year 2000 and 2004. Prior systemic chemotherapy regimens without paclitaxel or gemcitabine were acceptable. Radiation therapy was allowed as long as it was completed more than 1 month before enrollment, <25% of marrow-bearing areas were included and a previous radiation field had not overlapped to a measurable site used for assessment of chemotherapy response.
Before study entry, all patients underwent a complete history and physical examination, performance status score, symptom evaluation, complete blood count, biochemical test, urinalysis, creatinine clearance, chest and abdominal computed tomography scan, bone scan, chest X-ray and electrocardiogram. Requirement for patients included leukocyte count >3000/µl, neutrophil count >1500, platelet count >100 000/µl and hemoglobin level >10 g/dl, and serum alannine transferase and aspartate transferase levels less than twice the upper normal limits.
All patients who were enrolled in the study signed a written informed consent form. All of the procedures followed were in accordance with the ethical standards of the Institutional Review Board at the Kyoto University Graduate School of Medicine and the Declaration of Helsinki.
CHEMOTHERAPY REGIMEN
Gemcitabine (2'-deoxy-2', 2'-difluorocytidine; Eli Lilly Japan, Kobe, Japan) 2500 mg/m2 and paclitaxel (Taxol; Bristol-Myers Japan, Tokyo, Japan) 150 mg/m2 were given intravenously every 2 weeks. Dexamethazone 16 mg was administered in the first cycle and 8 mg for the following cycles. Antiemetics and other supportive therapies were administered at the discretion of the physician. If either white blood cell count of <2000 or granulocyte of <1000 was observed, granulocyte colony stimulating factor was administered. Before each cycle of chemotherapy, laboratory tests were conducted for hematological, hepatic and renal toxicities. Termination of treatment was considered in patients with white blood cell <2000 and/or platelets <75 000 cells/mm3 or inadequate hepatic or renal function. Hepatic function was determined from serum levels of bilirubin, ALP and AST. Renal function was determined from serum creatinine level and creatinine clearance.
RESPONSE AND TOXICITY CRITERIA
CT scan was performed to examine tumor size and new lesion at baseline and after two cycles or indicated clinically. All tumor evaluations for individual patients were performed using the same techniques at baseline and after each course. If partial response (PR) or complete remission was observed, chemotherapy was continued until disease progression or toxicity of Grade 3 or 4 was observed. All the patients who had received at least one cycle of therapy were considered assessable for toxicity. CR was defined as the complete disappearance of all clinically detectable disease measured by physical examination and/or radiographic study. PR required a decrease >50% in the sum of the products of the two greatest perpendicular dimensions of all measurable lesions. Progressive disease (PD) was defined as an increase >25% in the size of measurable lesions or the development of any new lesions; all other clinical situations were defined as no change (NC). Minor response was a part of NC and defined as response <50%. Toxicity grade was defined according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC), Version 2.0. The duration of response was calculated from the start of the GP regimen to the date of first evidence of disease progression. Survival was calculated from the start of the treatment for metastatic disease to death or to the last follow-up. The Kaplan–Meier method was used to assess overall survival.
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RESULTS |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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PATIENT CHARACTERISTICS
A total of 23 patients with metastatic urothelial cancer were enrolled in the study and received at least two cycles of GP regimen. Demographic and baseline characteristics for patients are presented in Table 1. The average age was 67 years (range 56–77). ECOG performance scores were 0 for 18 of 23 patients, 1 for three patients and 2 for two patients. The primary tumor sites were bladder in 12 patients, the upper urinary tract in 10 and both in one. Six patients (26%) had locoregional LN metastasis, while the remaining 18 patients (78%) had visceral metastasis (bone, liver or lung). The reasons we decided ineligible for cisplatin-based chemotherapy were: metastatic disease resistant to cisplatin-based chemotherapy regimen in 14 patients, heavy toxicities in prior cisplatin-based chemotherapy in three, ECOG performance score with 2 in two and impaired renal function in four. In 14 patients with cisplatin-resistant metastatic tumors, prior chemotherapies included modified M-VAC consisting of methotrexate, epirubicin and cisplatin (MEC) (7) in 11 patients, M-VAC in one patient, modified M-VAC consisting of methotrexate, vinblastin, epirubicin and cisplatin (M-VEC) (8) in one patient and single cisplatin in one patient. The median cycles of prior cisplatin-based regimen was 3 (range 1–8). Treatment response was evaluated after two cycles of GP regimen in 20 patients. In three patients, chemotherapy was discontinued because of the evident disease progression after one cycle. The median number of cycles administered was 2 (range 1–8). Median follow-up period was 14 months (range 5–62).
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RESPONSE
The overall response rate was 30% (95% CI 15.6–50.8%). No patient attained CR and seven patients had PR out of 23 patients. Eight patients (35%) had NC and eight patients (35%) had PD (Table 2). In 14 patients of the cisplatin-resistant group, PR was observed in two patients (14.2%, 95% CI 4.0–39.9%). In the remaining nine patients ineligible for cisplatin, PR was observed in five (55.5%, 95% CI 26.6–81.1%). The median duration of response was 4 months (range 3–8). However, one patient with PR refused to continue the treatment because of neuralgia. The median duration of survival for all patients was 12.1 months (95% CI 8.6–15.5). The measurable metastatic sites eligible for assessment of treatment response were: bone (3), liver (5), lung (10) and LN(10). Response according to disease site is shown in Table 3.
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TOXICITY
Frequencies of Grade 1 or 2, and Grade 3 adverse events are shown in Table 4. Grade 4 adverse events were not experienced. Leucopenia was the most common serious toxicity observed in six patients (26%). In six patients (26%) and eight of 73 cycles (11%), G-CSF was required. Bleeding episodes or anemia was not observed.
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Among non-hematological toxicity, neuralgia was the most common toxicity observed in nine patients (39%). All were Grade 1 or 2 and well controlled by NSAIDs. Three patients had interstitial pneumonitis possibly attributed to gemcitabine. In two patients, it disappeared without any treatment and one patient was successfully treated with corticosteroid.
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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RESPONSE
In this study, we observed that GP combination regimen was effective in patients with advanced urothelial cancer in which tumors were cisplatin-resistant or patients were ineligible for cisplatin-based chemotherapy. Table 5 summarizes dose, overall efficacy and toxicity of GP regimen in the literature. When overall response was roughly compared, our result is lower than that of Sternberg et al. and almost equal to that of Kaufman et al., although ratios of cisplatin-resistant to naïve patients were different among these studies. The overall response rate was 30%, 14.2% for cisplatin-resistant case and 55.5% for cisplatin ineligible cases. In the report of Sternberg et al. (6), overall response rate was 60%, 27% in 15 patients of cisplatin-resistant case and 80% in 25 patients treated by cisplatin-based regimen as neoadjuvant or adjuvant setting. In the recent report of the GP regimen by Kaufman et al. (9), 34% in 6 patients of cisplatin-resistant tumor and 41% in 49 patients who had not received any chemotherapy. In all of the three series, the response rate is higher in non-resisitant patients. The ratio of patients with visceral metastasis was 73% in this study, whereas it was 58% in the report of Kaufman et al. (9). Further study with larger scale is required to determine the response rate of GP regimen both for cisplatin-resistant group and non-resistant group. According to the original report of Sternberg et al., they used 2500 or 3000 mg/m2 of Gemcitabine biweekly and stated that they observed no difference in efficacy between the two groups of patients. We set the dose of gemcitabine as 2500 mg/m2; lower dose of the report, because we used GP regimen as second line to cisplantin-resistant case or palliative therapy for cisplatin-ineligible case. In addition, we thought it was more important to achieve safety rather than to raise efficacy. We admit that lower response rate of this study might be caused by this lower dose setting.
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In this study, we used GP regimen for patients ineligible for cisplatin-based regimen such as impaired renal function and poor performance status and observed high response rate. In practical clinical setting, we often encounter the situation that such advanced urothelial cancer patients need systemic chemotherapy. GP regimen can be a valuable treatment option for these patients. After GP regimen was reported, combination regimens of new agents without cisplatin have been investigated (2,10) such as gemcitabine and epirubicin (11,12) or gemcitabine and docetaxel (13–15). However, the response rate of the regimens was not superior to that of GP regimen. Although response rate in this study was lower than that of a report by Sternberg et al. (6), we believe that the GP regimen is still promising as a combination chemotherapy for cisplatin ineligible patients and deserves intensive study.
Patients with advanced urothelial cancer often have impaired renal function, due to high age, prior nephrectomy, hydronephrosis caused by involvement of ureter and other cause. Because of the renal toxicity of cisplatin, M-VAC cannot be the option of treatment for such patients. In our study, four patients with impaired renal function could be treated safely with GP regimen. This is one of major advantages of this treatment regimen. In addition, the GP regimen had only low-grade gastrointestinal side effects, which might make this regimen well tolerable on outpatient basis. Unlike gastrointestinal side effects, myelosuppression was observed in high frequency (26% of patients) and administration of G-CSF was required, which is slightly higher than reported data. This might be because more than half of the patients in this study had already received prior cisplatin-based chemotherapy.
Patients frequently complained of numbness of fingers and joint pain. These were rarely observed in M-VAC and other cisplatin-based combination chemotherapy. These side effects are reported to be temporary and would not be a dose limiting factor. However, especially, numbness of finger sometimes significantly deteriorates quality of life. More effective preventive methods would be required.
Interstitial pneumonia was observed in three patients. Among the three patients, one patient developed severe bilateral disease, which was consolidated with steroid pulse therapy. This patient had multiple pulmonary metastases and prior radiation therapy to mediasternal LN metastasis. Interstitial pneumonia is frequently reported in lung and other cancers in association with gemcitabine, and lung metastasis is one of the risk factors for pulmonary toxicity (16). Gemcitabine is known as radio-sensitizer and history of prior radiotherapy is also a risk for interstitial pneumonia (16,17). It is to be noted that the dose of gemcitabine in GP regimen is higher compared with regimens for lung and other cancers (18). Recently, Li et al. reported of weekly administration of GP for advanced urothelial cancer patients (19). The dose of GP was 1000 and 110 mg/m2/week and dose intensity was almost equal to the biweekly regimen in this study. While they observed considerably high response rate up to 69%, they did not recommend the regimen because of the high incidence of pulmonary toxicity. Schedule of administration as well as dose might have an influence on pulmonary toxicity. Considering high dose of gemcitabine and synergic effect of the two agents, we should be careful in considering the use of GP regimen for patients with possible risk factors of interstitial pneumonitis. In our case, mild dyspnea and slight change of SpO2 were the first signs of interstitial pneumonia identified a few days before appearance of abnormal shadow on plain chest X-ray and CT scan image. It is important to avoid this toxicity by careful history taking, physical examination and follow-up procedures such as frequent monitoring of SpO2 to observe the patients after GP treatment.
In conclusion, the GP regimen can be an effective and safe therapy for advanced urothelial cancer. GP regimen is effective in some patients with cisplatin-resistant tumors and promising as second line chemotherapy. GP regimen was more effective and well tolerated as first line chemotherapy in patients ineligible for cisplatin-based chemotherapy. Toxicity is generally mild but care must be taken for patients with risk of interstitial pneumonitis. Further study on a larger scale is required to confirm efficacy and survival benefit.
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