A feasibility study of carboplatin with fixed dose of gemcitabine in ‘unfit’ patients with advanced bladder cancer

doi:10.1016/S0959-8049(01)00295-7

European Journal of Cancer

Volume 37, Issue 17, 2001, Pages 2212-2215

https://doi.org/10.1016/S0959-8049(01)00295-7 Get rights and content

Abstract

For the purpose of a subsequent phase II/III European Organization for Research and Treatment of Cancer (EORTC) trial, a gemcitabine/carboplatin feasibility study in ‘unfit’ patients with advanced urothelial cell cancer was conducted. Gemcitabine was given at 1000 mg/m² days 1 and 8 with carboplatin (area under the curve (AUC) 4.5 or 5) day 1 every 21 days. 16 patients were treated, median age 68 years (47–75) years, performance status (PS) 0/1/2 in 3/10/3 patients. Creatinine clearance was >1 ml/s in 3 patients, 0.5–1 ml/s in 9 and <0.5 ml/s in 4 patients. Half of the patients had visceral disease. Median number of cycles given was 4 (range 2–6), for a total of 69 cycles. The first 8 patients received 33 cycles using a carboplatin AUC of 5. World Health Organization (WHO) grade 3-4 toxicity was: haemoglobin 5 patients, platelets 6 patients, neutrophils 5 patients and febrile neutropenia 2 patients. In view of this haematological toxicity in subsequent patients, the carboplatin AUC was decreased to 4.5. At this dose level, 8 patients received 36 cycles. WHO grade 3-4 toxicity was: anaemia 1 patient, platelets 4 patients, neutrophils 4 patients with no febrile neutropenia. Thus, this dose level was regarded to be feasible. For the 16 evaluable patients, overall response rate was 44%, (1 complete response (CR), 6 partial response (PR)). In conclusion, the combination of gemcitabine with carboplatin at an AUC of 4.5 appears to be an active and well tolerated regimen with acceptable toxicity in this unfit patient population. Based on these data, a randomised trial in the framework of the EORTC-Genitourinary (GU) group of gemcitabine/carboplatin versus carboplatin/methotrexate/vinblastine (MCAVI) is ongoing.

Introduction

For more than a decade, methotrexate/vinblastine/doxorubicin/cisplatin (MVAC) has been the standard chemotherapy regimen in the treatment of urothelial cell cancer [1]. As cancer of the urinary tract occurs especially in elderly frail patients, many of whom have impaired renal function and/or cardiovascular disease, a considerable number of patients with metastatic disease do not qualify for cisplatin-based chemotherapy. In particular, the presence of impaired renal function, older age, poor performance status or underlying cardiac dysfunction in the so-called ‘unfit’ patient population has led to several modifications of the standard cisplatin-based programmes.

Because of its favourable toxicity profile, carboplatin has been substituted for cisplatin in unfit patients and especially in those patients with compromised renal function. The overall response rate in these carboplatin-substituted studies is approximately 50% (range 45–63%) and the median reported overall survival is approximately 9 months 2, 3, 4, 5, 6.

Gemcitabine, a novel nucleoside analogue, has recently been recognised as a new active agent in urothelial cell cancer. This drug was initially evaluated in an Italian phase I study conducted in 15 patients with metastatic bladder cancer [7]. The doses ranged from 875 to 1370 mg/m². The overall response rate was 27%. In a subsequent phase II trial in previously treated patients, a response rate of 28% was recorded [8]. Two recent trials that evaluated gemcitabine in previously untreated patients confirmed the high activity of this agent. Stadler and colleagues treated 40 patients with gemcitabine 1200 mg/m² weekly times 3, repeated every 28 days, and reported an overall response rate of 28% [9]. Three complete responses (CRs) occurred in patients with liver metastasis. Moore and colleagues [10] reported an overall response rate of 24.3% (95% Confidence Interval (CI): 12–41%) in 37 assessable patients. In addition to its single agent activity in bladder cancer, gemcitabine is generally well tolerated. Furthermore, cisplatin/gemcitabine-based regimens are promising in advanced bladder cancer 11, 12 and provide similar activity and less toxicity than MVAC [12].

Hence, the combination of carboplatin and gemcitabine appears an attractive notion in patients with impaired World Health Organization (WHO)-performance status and/or impaired renal function. A feasibility study of the combination of gemcitabine/carboplatin in this particular patient population was conducted for the purpose of a subsequent phase II/III randomised trial in the framework of the European Organization for Research and Treatment of Cancer-Genitourinary (EORTC-GU) Group.

Section snippets

Patients

Eligibility criteria were: histologically-proven urothelial cell cancer of the urinary tract, distant metastases or pelvic disease not amenable to locoregional treatment and unfit for cisplatin-based combination chemotherapy for reasons of WHO performance status (PS) 2 and/or creatinine clearance below 1 ml/s. Patients had adequate bone marrow reserve, with an absolute neutrophil count (ANC) >1500×10⁶ cells/l and platelet count >100×10⁹ cells/l, and adequate hepatic and renal function (serum

Patient characteristics

Patient characteristics are shown in Table 2. From June 1997 to July 1998, a total of 16 patients were included in the study. The median age was 68 years (range 47–75 years). The reasons for offering treatment with this carboplatin/gemcitabine combination were poor WHO-PS in 3 patients (PS 2) and creatinine clearance <1 ml/s in 13 patients. 3 patients had received prior neoadjuvant/adjunvant chemotherapy and 2 patients had received prior chemotherapy for metastatic disease.

Toxicity

The median number of

Discussion

The EORTC-GU Group has recently defined separate investigational strategies in urothelial cell cancer for ‘fit’ versus ‘unfit’ patients. In patients unfit for cisplatin-based chemotherapy, a randomised study of gemcitabine/carboplatin versus carboplatin-MV was planned. To define a recommended dose of gemcitabine/carboplatin for this randomised trial, we conducted the present feasibility study in patients ‘unfit’ for cisplatin chemotherapy.

Carboplatin-based regimens are widely used as an

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Cervical cancer (CC) in Mexico is diagnosed mainly in locally advanced (LACC) and advanced (ACC) stages, where ureteral obstruction is more frequent. The standard treatment for this population is concurrent chemoradiotherapy (CCRT) with cisplatin, which is nephrotoxic and could lead to further deterioration of renal function in LACC patients with renal function decline. We aimed to evaluate the effect of CCRT with Gemcitabine on renal function in LACC patients.
This retrospective study included LACC patients treated with CCRT with Gemcitabine as a radiosensitizer from February 2003 to December 2018. Data were collected from medical archives and electronic records. We assessed renal function before and after CCRT treatment and analyzed the patient's response to treatment and survival.
351 LACC patients treated were included and stratified into two groups: 198 with Glomerular Filtration Rate (GFR) ≥60ml/min (group A) and 153 with GFR<60ml/min (group B). An improvement in GFR was observed after CCRT in patients in group B, from 33 ml/min to 57.5 ml/min (p<0.001). Complete response was observed in 64.1% of patients in Group A and 43.8% in Group B (p<0.0001). Factors associated with increased risk of death included having a GFR of 15-29 ml/min (HR: 2.17; 1.08-4.35), having GFR<15 ml/min (HR: 3.08; 1.63-5.79), and receiving Boost treatment (HR: 2.09; 1.18-3.69). On the other hand, receiving brachytherapy is a positive predictor for OS (HR:0.51; 0.31-0.84).
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Carboplatin Induction Chemotherapy in Clinically Lymph Node–positive Bladder Cancer
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There are currently no guideline recommendations regarding the treatment of cisplatin-ineligible, clinically lymph node–positive (cN+) bladder cancer (BCa).
To investigate the oncological efficacy of gemcitabine/carboplatin induction chemotherapy (IC) in comparison to cisplatin-based regimens in cN+ BCa.
This was an observational study of 369 patients with cT2–4 N1–3 M0 BCa.
IC followed by consolidative radical cystectomy (RC).
The primary endpoints were the pathological objective response (pOR; ypT0/Ta/Tis/T1 N0) rate and the pathological complete response (pCR; ypT0N0) rate. We applied 3:1 propensity score matching (PSM) to reduce selection bias. Overall survival (OS) and cancer-specific survival (CSS) were compared across groups using the Kaplan-Meier method. Associations between the treatment regimen and survival endpoints were tested in multivariable Cox regression analyses.
After PSM, a cohort of 216 patients was available for analysis, of whom 162 received cisplatin-based IC and 54 gemcitabine/carboplatin IC. At RC, 54 patients (25%) had a pOR and 36 (17%) had a pCR. The 2-yr CSS was 59.8% (95% confidence interval [CI] 51.9–69%) for patients who received cisplatin-based IC versus 38.8% (95% CI 26–57.9%) for those who received gemcitabine/carboplatin. For the pOR (p = 0.8), ypN0 status at RC (p = 0.5), and cN1 BCa subgroups (p = 0.7), there was no difference in CSS between cisplatin-based IC and gemcitabine/carboplatin. In the cN1 subgroup, treatment with gemcitabine/carboplatin was not associated with shorter OS (p = 0.2) or CSS (p = 0.1) on multivariable Cox regression analysis.
Cisplatin-based IC seems to be superior to gemcitabine/carboplatin and should be the standard for cisplatin-eligible patients with cN+ BCa. Gemcitabine/carboplatin may be an alternative treatment for selected cisplatin-ineligible patients with cN+ BCa. In particular, selected cisplatin-ineligible patients with cN1 disease may benefit from gemcitabine/carboplatin IC.
In this multicenter study, we found that selected patients with bladder cancer and clinical evidence of lymph node metastasis who cannot receive standard cisplatin-based chemotherapy before surgery to remove their bladder may benefit from chemotherapy with gemcitabine/carboplatin. Patients with a single lymph node metastasis may benefit the most.
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Citation Excerpt :
Impaired renal function, peripheral neuropathy, hearing loss, poor performance status, and inability to receive adequate hydration render approximately 30% of patients ineligible to receive cisplatin-based regimens. In these sicker patients, substitution with carboplatin-based regimens has shown encouraging efficacy and improved tolerability.4-9 Therefore, carboplatin-based regimens are an attractive backbone for clinical studies of additional agents with the aim of improving efficacy while maintaining acceptable tolerability.
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Subjects with metastatic or unresectable chemotherapy-naive TCC with Eastern Cooperative Oncology Group performance status 0 or 1 received gemcitabine (1000 mg/m² on days 1 and 8) and carboplatin (area under the curve of 5 on day 1) with sorafenib (400 mg 2 times a day on days 2-19 every 21 days) for 6 cycles. Subjects with stable disease or partial or complete response continued to receive sorafenib until disease progression. The primary end point was progression-free survival (PFS) at 5 months with a secondary end point of response (partial or complete).
Seventeen subjects were enrolled. The median number of cycles of gemcitabine and carboplatin with sorafenib provided was 4.4. A total of 15, 5, and 8 subjects required reductions of gemcitabine, carboplatin, and sorafenib, respectively. Thirteen subjects (76%) required multiple dose reductions. Eleven subjects (65%) were free of progression at 5 months. The overall response rate was 54% (95% confidence interval [CI], 0.28-077), with 4 patients experiencing complete response (24%; 95% CI, 0.07-0.50) and 5 partial response (29%; 95% CI, 0.10-0.56); 7 subjects (41%) had stable disease. Median PFS was 9.5 months (95% CI, 0.43-1.26), and median overall survival was 25.2 months (95% CI, 0.96-5.65). One-year PFS was 31%, and 1-year overall survival was 72%. Eleven subjects (65%) discontinued treatment because of toxicity. There were no toxic deaths.
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2017, Clinical Genitourinary Cancer
Although gemcitabine plus carboplatin (GCa) is the conventional first-line chemotherapy for cisplatin-ineligible metastatic urothelial carcinoma, its results are suboptimal. A meta-analysis evaluated the results of gemcitabine with either carboplatin or a taxane (GT). Literature was searched for studies including GT (paclitaxel or docetaxel) and GCa. We pooled trial level data including response-rate, progression-free survival, overall survival (OS), and Grade 3 to 4 side effects. Trial characteristics and outcomes were univariably compared between GT and GCa. Those factors, which were recorded in > 12 trials, were analyzed. Multivariable regression models were used adjusting for Eastern Cooperative Oncology Group performance status 2 and the presence of visceral metastases. Each trial was weighted by its sample size. Twenty-seven arms of trials totaling 1032 patients were selected, of which 13 contained GT (n = 484) and 14 GCa (n = 548). The percentage of patients with Eastern Cooperative Oncology Group performance status 2 was statistically significantly different between the 2 groups (median, 8.7% vs. 23.9%; P = .003). No efficacy outcome was statistically significantly different. Median OS was 13.2 months (range, 10-15.8 months) for GT and 10 months (range, 3.3-20 months) for GCa (P = .12). However, statistically significant increases in the frequency of Grade 3 to 4 anemia (P = .010) and thrombocytopenia (P = .010) for GCa, and neuropathy (P = .040) for GT were observed. No difference in OS according to treatment was found multivariably (P = .79). In this analysis, a similar response rate and survival and worse neurotoxicity were observed with GT compared with GCa, for which hematologic toxicity was more frequent. GT is an alternative to GCa for advanced cisplatin-ineligible urothelial cancer.
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Citation Excerpt :
A nonsignificant trend (p = 0.075) towards a better OS with the triple combination regimen was observed, although a larger trial may have potentially identified a statistically significant difference. Additional smaller phase 2 studies have reported results with either gemcitabine or platinum alone or in combination with paclitaxel or docetaxel [9–35]. Results with gemcitabine-platinum doublet as the standard arm of randomized phase 3 studies were also available [36–39].
Gemcitabine/platinum chemotherapy is the most widely used first-line regimen for metastatic urothelial carcinoma, and the potential improvement of adding taxanes needs to be clarified.
To study the survival impact of taxane plus gemcitabine/platinum compared with gemcitabine/platinum alone as upfront therapy.
Literature was searched for studies including gemcitabine/platinum ± taxanes (paclitaxel or docetaxel only). We pooled trial level data including the median, proportions, and confidence intervals on response-rate, progression-free survival, overall survival (OS), and side effects. Univariable and multivariable regression models evaluated the prognostic role of addition of taxanes after adjusting for platinum type, performance status 2, and the presence of visceral metastases. Data were weighted by the logarithm of the trial sample size.
Thirty-five arms of trials including 2,365 patients were selected (seven with taxanes [n = 617], and 28 arms without taxanes [n = 1,748]). Median OS was univariably significantly different (p = 0.019) between trials with and without taxanes. Across trials, the median ‘median OS’ amongst trials containing taxanes was 15.5 mo, compared with 12.5 mo in trials which did not. Multivariably, visceral disease and performance status were significantly associated with OS, and the addition of taxanes trended toward significantly better OS (p = 0.056) and increase in grade ≥ 3 neurotoxicity (p = 0.051), regardless of specific platinum agent used.
In this meta-analysis, adding taxanes to gemcitabine and platinum showed a trend for improved OS and higher grade ≥ 3 neurotoxicity. Improvements in patient selection and the evaluation of a more potent and tolerable tubulin inhibitor in combination with gemcitabine/platinum in a well-powered trial are the critical next steps.
In this report, a trend for improved overall survival and worse neurotoxicity was observed for adding a taxane to first-line gemcitabine/platinum chemotherapy for metastatic urothelial carcinoma. More effective taxanes should be investigated further in urothelial carcinoma in combination with gemcitabine/platinum.

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A feasibility study of carboplatin with fixed dose of gemcitabine in ‘unfit’ patients with advanced bladder cancer

Abstract

Introduction

Section snippets

Patients

Patient characteristics

Toxicity

Discussion

Eur. J. Cancer

Cancer Treat. Rev.

Annals. Oncol.

Eur. J. Cancer

Chemotherapy for advanced bladder cancer

Semin. Oncol.

Carboplatin, methotrexate and vinblastine (Carbo-MV) for advanced urothelial cancer

Am. J. Clin. Oncol.

Carboplatin, methotrexate, and vinblastine in patients with bladder cancer who were ineligible for cisplatin-based chemotherapy

Cancer

A carboplatin-based regimen for the treatment of patients with advanced transitional cell carcinoma of the urothelium

Cancer

Phase II study of single-agent gemcitabine in previously untreated patients with metastatic urothelial cancer

J. Clin. Oncol.

Gemcitabinea promising new agent in the treatment of advanced urothelial cancer

J. Clin. Oncol.