Annals of Oncology Advance Access originally published online on September 12, 2006
Annals of Oncology 2006 17(11):1687-1692; doi:10.1093/annonc/mdl286
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© 2006 European Society for Medical Oncology
urogenital tumors |
Sequential gemcitabine and cisplatin followed by docetaxel as first-line treatment of advanced urothelial carcinoma: a multicenter phase II study of the Hellenic Oncology Research Group
1 Second Department of Medical Oncology, "Theagenion" Cancer Hospital of Thessaloniki, Thessaloniki
2 Department of Medical Oncology, University General Hospital of Heraklion, Heraklion; Crete
3 First Department of Medical Oncology, "Metaxa", Anticancer Hospital, Pireas
4 First Department of Propedeutic Medicine of University of Athens, Medical Oncology Unit, "Laikon" Hospital, Athens, Greece
*Correspondence to: Dr I. Boukovinas, Second Department of Medical Oncology, "Theagenion" Cancer Hospital of Thessaloniki, 2 Symeonidou Street, 54007 Thessaloniki, Greece. Tel: +30 2310 898605; Fax: +30 2310 898608; E-mail: ibouk{at}otenet.gr
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Abstract |
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Background: The purpose of this study was to investigate the toxicity and efficacy of the sequential administration of gemcitabine (GMB) in combination with cisplatin (CDDP) followed by docetaxel (Taxotere) as first-line treatment of advanced urothelial carcinoma.
Patients and methods: Patients [aged 
70 years and performance status (PS) (Eastern Cooperative Oncology Group) 0–2] with previously untreated locally advanced/recurrent or metastatic urothelial carcinoma were eligible. Study treatment consisted of GMB (1000 mg/m2, days 1 and 8) and CDDP (70 mg/m2, day 1) (GP regimen), every 21 days for a total of four cycles followed by docetaxel (D; 100 mg/m2, day 1) every 21 days for four cycles.
Results: Thirty-eight patients with a median age of 67 years were enrolled; 67% of them had PS 0 and 87% stage IV disease. Patients received a median of four GP and four D cycles per patient. Grade 3–4 neutropenia occurred in 27% and 63% patients with GP and D, respectively. Grade 3–4 thrombocytopenia occurred in 11% of patients, only with the GP regimen. Other toxic effects were mild. There was no toxic death. The objective response rate was 55.2% [95% CI: 39.45%–71.07%]. Five patients had complete response (13.15%) and 16 patients had partial response (42.1%), while nine patients had disease stabilization (23.7%) (intention-to-treat analysis). After a median follow-up period of 13 months (range 1.5–40.5 months), the median time to progression was 6.8 months (range 1–40.5 months), the median overall survival 13 months (range 1.5–40.5 months), and the 1-year survival rate 55.3%.
Conclusion: The sequential administration of GP followed by D is active and well tolerated as first-line treatment of advanced urothelial carcinoma and merits to be further evaluated.
Key words: bladder cancer, cisplatin, docetaxel, gemcitabine, transitional cell carcinoma
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introduction |
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Although infiltrative urothelial carcinoma is a relatively chemosensitive neoplasm, it still remains a fatal disease since
50% of all patients will develop local or/and distant metastases [1–3]. Furthermore, despite response rates of up to 70% could be achieved with cisplatin (CDDP)-based chemotherapy, >80% of the patients will die of progressive cancer [4]. Unfortunately even with the incorporation of newer regimens, the 5-year disease-free survival rate has not been improved [1, 4–6]. Therefore, several studies evaluating variations on the current standard of care are being investigated in order to improve efficacy. The combination of methotrexate-vinblastine-adriamycin-cisplatin (M-VAC regimen) has been shown to improve the survival of patients with advanced urothelial cancer representing the standard of care during the last 15 years. However, the efficacy of M-VAC is achieved at the expense of severe toxicity, including myelosuppression, nausea, vomiting and nephrotoxicity [1, 7, 8]. A new alternative for the treatment of urothelial carcinoma is the combination of CDDP and gemcitabine (GMB) (GP regimen) which, with significantly less toxicity, has recently proven as efficacious as the classic M-VAC regimen, especially in terms of overall survival (OS) and time to tumor progression [9].
Since the GP regimen represents an alternative frontline treatment of urothelial carcinoma, the therapeutic efforts are now focused on the improvement of its effectiveness by adding a third drug [10]. A number of studies have shown that triple drug combinations may result in response rates of 50%, and median survival times of up to 14 months, both ifosfamide and taxanes [docetaxel (Taxotere; Sanofi-Aventis, Bridgewater, NJ) and paclitaxel (Taxol; Bristol-Meyers Squibb, NJ)] have demonstrated important activity against urothelial cancer [11–16], but the three drug regimens are associated with increased toxicity. Docetaxel has also shown significant antitumor activity as single agent [17, 18], or in combination with other agents in urothelial cancer [19–21]. On the basis of these data, the Urogenital Working Group of the Hellenic Oncology Research Group decided to conduct a multicenter phase II study in order to investigate the efficacy and toxicity of the sequential administration of the GP regimen followed by docetaxel (D regimen) in chemo-naive patients with locally advanced or metastatic urothelial carcinoma. The rationale for choosing this schedule is to deliver the maximum tolerated doses of three active drugs up front with the less associated toxicity.
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patients and methods |
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patient selection
Chemotherapy-naive patients, aged
70 years with histologically confirmed locally advanced/recurrent or metastatic transitional cell carcinoma were enrolled into the study. Patients had to have measurable or evaluable disease and a performance status (PS) [Eastern Cooperative Oncology Group (ECOG)] 0–2. Previous neo-adjuvant or adjuvant treatment was allowed as long as there was at least a 6-month treatment-free interval. Patients with a history of a second primary tumor, other than a nonmelanoma skin cancer or radically excised in situ carcinoma of the uterine cervix, with severe heart failure, arrhythmias or acute myocardial infarction within the previous 6 months, as well as patients with renal or liver failure (creatinine >1.5 mg/dl or creatinine clearance 60 ml/min, bilirubin >3 mg/dl, transaminases 2x upper normal limit) were excluded from the study. Other exclusion criteria were pregnancy, an abnormal bone marrow function (<1500 per dl neutrophils and 100.000 platelets), active infections or other serious underlying medical or mental conditions, which would impair their compliance to the protocol. The protocol has been approved by the Ethics and Scientific Committees of the participating Institutions and signed informed consent was obtained from all patients before study entry.
treatment schedule
Cisplatin (Platinol; Bristol-Myers Squibb, NJ) 70 mg/m2 was given on day 1 after appropriate hydration; Gemcitabine (Gemzar; Elli Lilly, Indianapolis, IN) was administered at the dose of 1000 mg/m2 by a 30-min i.v. infusion on days 1 and 8 (PG regimen). The combination was repeated every 21 days for a total of four cycles. Subsequently, docetaxel (D regimen) (Taxotere; Sanofi-Aventis, Bridgewater, NJ) was administered at the dose of 100 mg/m2 as a 1-h i.v. infusion, with appropriate standard premedication, on day 1 every 21 days for a further four cycles. The prophylactic use of hematopoietic growth factors [granulocyte colony-stimulating factor (G-CSF)] was not allowed. Supportive care, including blood transfusions, analgesics and antiemetics, was administered as appropriate. Patients received a total of eight (four GP and four D) chemotherapy cycles unless disease progression or unacceptable toxicity occurred.
dose modifications
Toxicity was evaluated before each treatment cycle according to the National Cancer Institute Common Toxicity Criteria (NCI CTC version 2.0). Dosage adjustments were made before each treatment on the basis of hematological and non-hematological toxicity. Patients requiring dose reductions were treated with reduced doses for all subsequent cycles. In case of grade 3 or 4 neutropenia, patients received the subsequent cycles of chemotherapy with prophylactic administration of G-CSF from day 2 to day 8 (Granocyte; 15 µg/m2; Sanofi-Aventis, NJ). This was chosen because we wanted to maintain dose intensity of active drugs since it has been described in randomized trials that long survivors may be patients achieving a complete response (CR) [22]; therefore, administering hematopoetic growth factors might allow a greater dose delivery which may be associated with a higher probability to achieve a CR. If grade 3 or 4 neutropenia occurred despite the subsequent administration of G-CSF as well as in case of febrile neutropenia, a 25% dose reduction was performed. A 25% dose reduction was also performed in case of grade 4 thrombocytopenia as well as in case of grade 3 or 4 non-hematologic toxicity. In case of nephrotoxicity, treatment was postponed until recovery of the renal function; in subsequent cycles, carboplatin (AUC 6 area under the curve) was substituted for CDDP.
response evaluation
Baseline evaluation included a complete medical history and physical examination electrocardiogram, chest X-rays, computed tomography scans of the thorax and upper/lower abdomen, a whole-body bone scan, as well as complete blood cell count with differential and platelet count, renal and liver function tests. During treatment, renal and liver function tests were performed before each cycle while complete blood cell count with differential and platelet count and serum creatinine levels were followed in a weekly basis.
Tumor assessment was performed after the administration of the four GP and after the four D cycles, unless earlier evaluation was required. Dose intensity was defined as the total amount of the drug (mg/m2) given per week. All patients were analyzed on an intention-to-treat basis. Patients were assessed for response using standard World Health Organization response criteria. Patients who discontinued treatment before tumor assessment or those who were lost to follow-up were considered as nonresponders. All adverse events resulting in discontinuation were followed closely until resolution or stabilization. After treatment completion, all patients were followed-up at least every 3 months with biochemical and imaging studies until disease progression or death.
statistical analysis
The primary end point of this phase II study was objective response rate (ORR) and secondary end points OS, time to progression (TTP) and toxicity. The sample size was calculated on the assumption that a 40% response rate would be detected and the minimum acceptable response rate would be 20%. According to the Simon's two-stage design model, a sample of 18 patients was required in the first part of the study; if a minimum of five responses were observed, a total of 33 patients would be accrued. Therefore, if at least 11 responses occurred, the probability of accepting a treatment with a real response rate of <20% would be 5%. On the other hand, the risk of rejecting a treatment (at the second part of the trial) with a response rate of >40% would be 20%. The time to disease progression (TTP) was calculated from the initiation of treatment to the date of the documentation of disease progression (patients who discontinued their treatment of any reason or died from probable disease-related causes were considered, at that time, as having disease progression). Survival was calculated from initiation of treatment to the date of last contact or to the date of death. The Kaplan–Meier method [23] was used to calculate TTP and survival curves and exact CIs [24] were used to determine the 95% upper and lower CIs of response rate. Data analysis was performed using SPSS 10.5 (SPSS, Inc., Chicago, IL).
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results |
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patient characteristics
Between March 2001 and February 2004, 38 chemotherapy-naive patients with locally advanced/relapsed or metastatic urothelial carcinoma were enrolled onto this multicenter phase II study. Final data analysis was performed 11 months after the last patient was enrolled. The main patient baseline characteristics are summarized in Table 1. More than 95% of patients had an ECOG PS of 0–1 and 87% of the patients had stage IV disease; 21 (55%) patients had disease confined to the pelvis. In addition, 11 (29%) patients presented with both local and distant disease and 13 (34%) with multiple site involvement. Eleven (29%) patients had prior surgery, and three (8%) had received prior adjuvant chemotherapy or/and radiotherapy.
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compliance with the treatment
A total of 250 chemotherapy cycles were administered. Patients received a median number of eight (range 2–8) cycles of chemotherapy (a median of four GP cycles per patient and four D cycles per patient). Reasons for treatment discontinuation included disease progression or recurrence (n = 7 patients) and consent withdrawn (n = 4 patients). GMB and CDDP doses were reduced or omitted in 11 (8%) cycles for hematological (n = 3) and non-hematological (n = 2) toxicity or other reasons (n = 6). Treatment delay was necessary in 30% of GP cycles because of hematological (n = 6) and non-hematological (n = 3) toxicity or other reasons (n = 33) not related to treatment or toxicity. The median interval between GP cycles was 23 days (range 21–39). The median-delivered dose intensity was 581 mg/m2/week (range 337–667 mg/m2/week) for GMB and 21 mg/m2/week for CDDP (range 12–23 mg/m2/week), corresponding to the 87% and 92% of the protocol-planned dose, respectively. Two patients shifted to carboplatin after the first cycle due to impaired renal function and increase of serum creatine levels.
Docetaxel doses were reduced or omitted in two (2%) cycles for hematological (n = 1) and non-hematological (n = 1) toxicity. Treatment delay was necessary in 20% of D cycles because of hematological toxicity (n = 3) or other reasons not related to treatment (n = 17). The median interval between D cycles was 21 days (range 21–29). The median-delivered dose intensity for docetaxel was 30 mg/m2/week (range 16–33 mg/m2/week) corresponding to the 88% of the protocol-planned dose.
toxicity
All patients were evaluable for toxicity (Table 2). Severe (grade 3 and 4) neutropenia occurred in 10 (26%) and 19 (63%) patients following GP and D regimens, respectively. There was one patient who developed febrile neutropenia after D administration. A total of 30 patients received G-CSF during treatment because of neutropenic episodes. Grades 3 and 4 thrombocytopenia occurred in four (11%) patients after GP administration; however, no patient required platelet transfusions of hospitalization for bleeding problems. There was no toxic death. The incidence of severe (grade 3 or 4) non-hematological toxic effects was low (usually <5%).
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efficacy
All patients were evaluated for response (intention-to-treat analysis). Overall, the observed best response after the completion of the two parts of treatment was as follows: five (13.1%) patients achieved a CR and 16 (42.1%) a partial response (PR) (overall response rate 55.2%; 95% CI 39.45% to 71.07%); additionally, stable disease (SD) was observed in nine (23.7%) patients and progressive disease in eight (21.1%). Objective responses obtained with each sequential arm of chemotherapy are presented in Table 3. Two patients experiencing PR and one patient with SD after four initial GP cycles achieved a CR with D. In addition, one patient with disease progression under the GP regimen achieved a PR with D, while in four other patients already experiencing PR after GP, the clinical response was improved with D. Responses were seen at all sites of disease.
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After a median follow-up period of 13 months (range 1.5–42 months), 35 (92.1%) patients presented disease progression and 33 (86.8%) have died. The median TTP was 6.8 months (range 1.0–40.5 months) and the median OS 13 months (range 1.5–42). The actuarial 1-year and 2-year survival rates were 55.3% and 13.6%, respectively (Figure 1). Among the five alive patients, one had experienced CR and one PR under GP treatment and maintained the response with the administration of D (OS until now 36 and 31 months, respectively); in two other patients, D administration converted the response to GP regimen from PR and SD to CR (OS until now 35.4 and 42 months, respectively). Moreover, one patient experiencing SD during the whole sequence of treatment is still alive after 30 months of follow-up.
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discussion |
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Data from several phase II studies and a landmark phase III study have confirmed the clinical benefit of the combination of CDDP and GMB (GP regimen) in metastatic transitional cell urothelial cancer. The median survival obtained with GP regimen is
13 months; however, there is no significant improvement of long-term survival with this regimen [22]. In the present study, we aimed to improve the efficacy of the GP regimen by administering a taxane, with proven efficacy in urothelial cancer, sequentially to four GP cycles. One of the potential limitations of using all the drugs in combination is that generally the doses are reduced in order to limit the overlapping toxicity. Additionally, according to Norton and Day work [25], the sequential use of drug combination was predicted to outperform alternating cycles, because no two drug combinations were likely to be strictly non-cross-resistant or have equal cell-killing capacity, the symmetry assumed in the Goldie–Goldmann model. There is now a growing evidence of clinical examples, e.g. in breast, ovarian and colon cancer, which supports the notion that sequential chemotherapy represents a reasonable treatment option [27, 31].
In terms of response, the observed ORR for the GP regimen is in agreement with several previous studies [21, 24, 28]; however, the observed CR rate of 5.3% was much lower than it has been previously reported. This could be due to the administration of only four GP cycles in the current study compared with six to eight GP in other studies [21, 24, 28]. The question of optimal duration of treatment remains unanswered in bladder cancer. In the study of Kaufman et al. [24], only 50% completed six cycles of therapy and in the trial of Moore et al. [28], the median number of cycles was five comparing with the median of four for this study. However, the sequential administration of four cycles of docetaxel, resulted in an increase of the CR rate from 5% to 16.6%. These results are in agreement with those obtained with chemotherapy regimens combining GMB, CDDP and a taxane [11, 13, 30]. An interesting observation seem to be that this improved response rate was noticed in a group of patients where the majority (87%) of them had extensive disease. In all these studies, the ORR obtained with the triple combination of GMB, CDDP and a taxane [docetaxel or paclitaxel (Taxol, Bristol-Myers Squibb, NJ)] ranged from 65.6% to 77.6% [11, 13, 16]; only the study of Frassoldati et al. [30] reported an ORR of 16.6%. The reasons for this discrepancy are not obvious. In addition, the triple combination of GMB, CDDP and taxanes resulted in a median OS ranging from 14.7 to 24 months (that reported in the study of Belmunt et al. median OS of 24 months, concerned only the 15 patients of the phase I part of the study) [11, 13, 16]; the median OS observed in the current study of sequential administration of GP and D is consistent with the data of the literature with an overall favorable toxicity profile. The increase of the CR rate could account for the improved long-term survival observed in the current study, as previous studies have shown that among the patients who achieve a CR there is a small but significant percentage of them who will have a long-term survival. Another important observation is that some patients who achieved PR or SD after the first four GP cycles, showed disease progression under docetaxel treatment indication that, although, the monotherapy in the second part of the protocol may be active in some patients needs to be reinforced in others. Molecular or genetic tumor characteristics may be responsible for this heterogeneous effect of docetaxel.
The above efficacy results were obtained with an acceptable toxicity profile; indeed, the sequential administration of GP regimen followed by docetaxel was well tolerated. Overall, the incidence of 
grade 3 neutropenia during the administration of GP regimen was 26% and during the administration of D 63%. There was only one episode of febrile neutropenia after administration of D requiring hospitalization. However, most of the patients received G-CSF support during the neutropenic episodes which could probably explain the low incidence of febrile neutropenia. Also this could probably attribute to the frequent prophylactic use of G-CSF support. It should be noticed that docetaxel was given at the dose 100 mg/m2, on the basis of previous studies [17]. This dose is more toxic than 75 mg/m2 which is usually used in other types of cancer; however, there is no clear evidence that there is a dose–effect relationship of taxanes in urothelial cancer. These data compare with the levels of toxicity encountered when administering the three agents concurrently. As it concerns the non-hematologic toxicity, it was mild and easily manageable.
There has been much recent interest in the development of sequential chemotherapy schedules intended to improve the outcome of patients with urothelial cancer. These studies evaluated both the question of dosage but also the sequence itself. DiPaola et al. [25] has recently reported that the superior schedule and sequence in urothelial carcinoma is GMB + paclitaxel followed by carboplatin. In their study, paclitaxel and GMB were given on days 1, 8 and 15 and carboplatin on day 2 in cycles of 28 days. The authors indicated first in vitro that the efficacy was superior when CDDP followed paclitaxel; this observation indicates that the efficacy of paclitaxel would be decreased in cells pretreated with CDDP as a result of their arrest in S and not G2/M phase [30]. Indeed, an understanding of cell cycle inhibition and the efficacy of each chemotherapeutic agent should be an important consideration in the development of sequential chemotherapeutic schedules. Recently, several studies evaluating the sequential administration of chemotherapy regimens are ongoing and their results are eagerly awaited. On the basis of this interest in triplet combinations and sequential schedules in advanced transitional cell carcinoma, our study adds to the existing and ongoing knowledge with the utilization of a novel, effective and well-tolerated sequential schedule that warrants further development and evaluation.
Received for publication March 28, 2006. Revision received June 30, 2006. Accepted for publication July 3, 2006.
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