© 2004 Foundation for Promotion of Cancer Research
FOLFOX-4 in Pre-treated Patients with Advanced Transitional Cell Carcinoma of the Bladder
1 Cattedra di Oncologia Medica, Dipartimento di Endocrinologia e Oncologia Molecolare e Clinica and2 Clinica Urologica, Seconda Università degli Studi, Naples, Italy
For reprints and all correspondence: Giuseppe Di Lorenzo, Dipartimento di Endocrinologia e Oncologia Molecolare e Clinica, Università degli Studi di Napoli Federico II, Naples, Italy. E-mail: giuseppedilorenzoncol{at}hotmail.com
Received August 27, 2004; accepted September 23, 2004
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Abstract |
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 TOP Abstract INTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONReferences |
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Background: Despite recent progress in the treatment of advanced urothelial cancer, there continues to be a need to identify new active agents and their toxicity spectra. We conducted a study using FOLFOX-4 (oxaliplatin, fluorouracil, folinic acid) in pre-treated advanced bladder cancer patients.
Methods: Sixteen eligible patients with advanced disease were treated with oxaliplatin (85 mg/m3) on day 1 followed by fluorouracil and folinic acid (De Gramont schedule) on days 1 and 2 every 14 days until disease progression. All patients received nutritional support to increase their caloric intake. Objective responses and toxicity were evaluated. Biochemical responses (reduction of markers) and nutritional parameters (increase in body weight and albumin, and reduction in ferritin and C-reactive protein) were also considered.
Results: Three patients obtained an objective response (overall response rate 19%). Hematological toxicity and stomatitis were the most commonly noted side effects, but we observed only low (3–4) grade toxicity. In four patients (25%), we observed a reduction in tumoral markers (carcinoembryonic antigen and tissutal polypeptide antigen) and modified nutritional parameters.
Conclusions: Using these doses and schedules of FOLFOX-4 appears to be a promising therapy in patients pre-treated with platinum compounds. More studies are required to assess the possible role of this regimen in the treatment of advanced bladder cancer.
Key Words: chemotherapy • advanced disease • bladder cancer
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INTRODUCTION |
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TOPAbstractINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONReferences |
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Bladder cancer is the second most common genitourinary tumour and is a significant cause of morbidity and mortality. A total of 56 500 patients were diagnosed in the USA in 2002, of whom 12 600 were estimated to have died of the disease (1). The standard treatment for muscle-invasive bladder cancer is radical cystectomy and bilateral pelvic lymph node dissection. Although surgery may be curative,
50% of the patients with muscle-invasive transitional cell carcinoma develop metastases within 2 years of cystectomy and subsequently die of the disease (2).
At present, systemic combination chemotherapy is the only treatment that may result in long-term survival in some patients with advanced metastatic disease. Combination regimens including cisplatin and methotrexate, which are considered the most active single agents for treating this malignancy, result in an overall response rate of 50% in chemotherapy-naïve patients with a 20% complete response (3). Nevertheless, survival beyond 5 years is rare. The M-VAC regimen (comprised of methotrexate, vinblastine, doxorubicin and cisplatin) is considered the most active treatment (4) but to reduce its toxicity this standard has been compared with cisplatin–gemcitabine (CG) in a phase III trial (5). The study has shown that CG results in a similar survival to M-VAC but has a better safety profile and is better tolerated, confirming the view that the most active drugs in advanced urothelial cancer are platinum compounds.
Prognosis is dismal in patients with progressive disease after first-line chemotherapy. Over the last 10 years, however, a large number of new agents and combination regimens have been tested in patients with advanced urothelial carcinoma refractory to cisplatinum. Several of these agents, including paclitaxel, gemcitabine and docetaxel, have exhibited activity against advanced transitional cell carcinoma (6–8).
Recent phase II studies evaluating second-line chemotherapy have demonstrated objective response rates in the range of 10–25% for a variety of single agents and combination regimens (9–11).
Concomitantly, there has been an increased utilization of neoadjuvant and adjuvant chemotherapy, resulting in an increasing proportion of pre-treated relapsing patients. Thus, if we consider a relapsed patient, who has been already been submitted to adjuvant or neoadjuvant chemotherapy with platinum compounds, the treatment for his/her metastatic disease should represent a second-line chemotherapy in the history of this patient.
In the present study, we considered pre-treated patients with two lines of chemotherapy (adjuvant chemotherapy with M-VAC and, after the first relapse, with gemcitabine and taxoid compounds) to evaluate if those with a good performance status (PS) could be responsive to platinum compounds for the second time with a good tolerability. We used oxaliplatin, as platinum compound, because trials in other cancers have shown a good tolerability in pre-treated patients (12–14); 5-fluorouracil (FU) has been studied in bladder cancer and, as observed in other malignancies, it has clinical synergism with metal compounds, notably cisplatin (15,16). Oxaliplatin alone has a limited efficacy as single agent in second-line therapy, but the FOLFOX regimen (combination of FU, folinic acid and oxaliplatin) has demonstrated strong activity in patients previously treated for metastatic colon cancer. This regimen has given a response rate from 20% up to >40% and median survival between 10 and 17 months (17–19). A randomized study has shown that the combination of FUFA schedule with oxaliplatin (FOLFOX-4) prolonged progression-free survival (20).
Thus, we evaluated the activity and tolerability of combination chemotherapy with oxaliplatin, 5-FU and folinic acid (FOLFOX-4) in previously treated patients with advanced bladder cancer.
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SUBJECTS AND METHODS |
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Patients with histologically confirmed advanced transitional cell carcinoma of the bladder in whom platinum-based chemotherapy had previously failed were eligible for the study. All patients were pre-treated with gemcitabine and taxoid compounds as first line for metastatic disease.
Additional study inclusion criteria were bidimensionally measurable disease, adequate bone marrow, renal and hepatic functions with a leukocyte count of 
3000/mm3, platelet count 100 000/mm3, serum glutamic-oxaloacetic transaminase 
70 U/ml, serum bilirubin 2 mg/dl, serum creatinine 2 mg/dl and creatinine clearance 60 ml/min. Carcinoembryonic antigen (CEA) and tissutal polypeptide antigen (TPA) value, as humoral markers, was recorded before the treatment and every three cycles.
All patients were required to provide written informed consent before study entry.
Each cycle comprised a 2 h infusion of 85 mg of oxaliplatin (Eloxatin, Sanofi-Synthelabo) per m2 on day 1 followed by a 2 h infusion of 200 mg of leucovorin/m2 of body surface area (days 1 and 2), followed by a bolus of 400 mg/m2 of FU (days 1 and 2) and then a 22 h infusion of 600 mg/m2 of FU given on two consecutive days (De Gramont schedule). Chemotherapy was repeated every 2 weeks.
A nutritional support to increase the caloric intake was offered to patients. Each patient received two bricks/day (Prosure) (each 200 ml brick contained 200 kcal).
Baseline evaluation included a complete history and physical examination. Performance status was classified according to the World Health Organization (WHO) score. Patients were evaluated every 2 weeks with a physical examination of the body (weight measure), with a complete blood cell count, creatinine, serum glutamic-oxaloacetic transaminase, serum bilirubin, albumin, ferritin and C-reactive protein (CRP) levels.
The extent of tumor involvement was assessed by total body computed tomography (CT) after 6 cycles.
Complete response was defined as the disappearance of all tumoral lesions for a minimum of 4 weeks. Partial response was defined as a decrease of 50% in the sum of the products of the perpendicular diameters of all lesions for at least 4 weeks without a simultaneous increase in an existing lesion or the appearance of any new lesion. A tumor marker response was defined as a decrease of 50% from the pre-treatment value. Stable disease was considered a decrease in tumor mass of <50%, or an increase of 25%. Disease progression was defined as a >25% increase in tumor size, the appearance of any new lesion or biochemical evidence of worsening disease. Biochemical evidence of an increase in markers (>25% increase) (after three cycles) led to treatment being stopped and strumental evaluation.
When a partial or complete response or subjective improvement was achieved, patients received additional courses of chemotherapy until disease progression. Otherwise chemotherapy was stopped and palliative support care was initiated. National Cancer Institute (NCI) common toxicity criteria were used to analyze toxicity.
Survival was determined from the date of registration until the date of death. The duration of response was calculated from the time the response criteria were met until disease progression or the date the patient was last known to be in disease remission.
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RESULTS |
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TOPAbstractINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONReferences |
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We enrolled 10 men and six women of 50–80 years old (median age 63 years) with advanced transitional cell carcinoma of the bladder. Table 1 shows baseline patient characteristics. All of them had been treated with adjuvant chemotherapy and had also received previous chemotherapy for metastatic disease. Radiotherapy had been given in the adjuvant setting in only six patients. All had shown an increase in tumor markers (CEA and TPA). Secondary lesions developed in all cases after first-line therapy for advanced disease.
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Table 2 shows response data. A partial response was achieved in three patients for an overall response rate of 19%. Disease was stable in three additional patients (19%). The three responders presented partial response in liver (two), in lung (one) and in retroperitoneal sites (two patients). All the three responders continued chemotherapy until 10 cycles when we observed disease progression. A reduction in markers was observed in four patients (three patients with partial response and one patient with stable disease) after six cycles. In the same four patients, we have also observed an increase in appetite and albumin (1 g), and a reduction in ferritin and CRP. Median overall survival in the 16 patients was 4 months (range 2–8 months).
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All patients were evaluable for toxicity studies (Table 3). The major toxicity was NCI grades 3 and 4 granulocytopenia developed in 18% of the patients. Anemia was observed in 50% of patients, but only 6% of patients presented grade 3–4. Stomatitis, constipation and paresthesias were noted in 31, 19 and 19%, respectively considering all toxicity grades, with 0, 6 and 12% grade 3–4 toxicity.
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DISCUSSION |
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TOPAbstractINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONReferences |
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Patients with advanced urothelial cancer who fail to respond or who have relapse after first-line cisplatin-based chemotherapy have a grim prognosis with a life expectancy of <1 year (3). Various second-line regimens have been studied in an attempt to find promising new combinations or single agents that may result in an objective response or useful palliation in this setting (6–11). However, to achieve any symptomatic benefit in previously treated patients, the salvage regimen must involve acceptable toxicity.
Today many patients with bladder cancer are treated with chemotherapy in the adjuvant or neoadjuvant setting with platinum compounds. When the patients have relapse of disease, they are treated with new drugs as first-line chemotherapy for metastatic disease. Is it possible to treat the patients with platinum compounds again?
We chose oxaliplatin as the platinum compound because pre-treated patients have a good tolerability when they are treated with this drug (12–14). Oxaliplatin has demonstrated strong activity in previously treated patients with metastatic colon cancer in combination with FU (17–19).
Only one trial so far has reported the use of oxaliplatin in advanced bladder cancer. In this trial, Culine et al. treated the patients with gemcitabine and oxaliplatin as first-line chemotherapy, showing that this regimen was a safe therapy (21).
5-FU has been studied in pre-treated bladder cancer (15,16). In the trials of Huan et al. (22) and Otto et al. (23), second-line chemotherapy with FU had no effect on refractory metastatic bladder cancer, while in the trial of Logothetis et al. (24), FU in combination with 
-interferon appeared to be an effective treatment.
5-FU has not been studied in combination with oxaliplatin in pre-treated bladder cancer.
We performed a study to determine the activity and tolerability of combination chemotherapy with oxaliplatin, 5-FU and folinic acid (FOLFOX-4) in patients previously treated with platinum compounds. Three patients achieved an objective response for an overall response rate of 19%. This response rate is low if we compare it with FOLFOX-4 in colon cancer (17–19) but it is important to consider that the treatment was a third line and that those patients were pre-treated with platinum compounds.
Hematological toxicity and stomatitis were the most commonly noted side effects, but low grade 3–4 toxicity was observed. Considering that the patients were pre-treated with two lines of chemotherapy, the toxicity profile is good. In four patients (25%), we observed a reduction in tumoral markers and modified nutritional parameters.
Using these doses and schedules, the FOLFOX-4 regimen appears a promising therapy in patients pre-treated with platinum compounds. In our experience, it was an interesting third-line chemotherapy in terms of responses and toxicity. In this respect, it will be interesting to evaluate this treatment as a first-line treatment of metastatic disease or in an adjuvant setting, comparing FOLFOX with a cisplatin regimen. More studies are required to assess the future role of FOLFOX in advanced bladder cancer.
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References |
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TOPAbstractINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONReferences |
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