Med Oncol (2014) 31:811 DOI 10.1007/s12032-013-0811-5
ORIGINAL PAPER
Low-dose versus standard-dose gemcitabine infusion and cisplatin for patients with advanced bladder cancer: a randomized phase II trial—an update Rasha Haggag • Kamel Farag • Fouad Abu-Taleb Sameh Shamaa • Abdel-Rahman Zekri • Tarek ELBolkainy • Hussein Khaled
•
Received: 12 September 2013 / Accepted: 4 December 2013 / Published online: 12 December 2013 Ó Springer Science+Business Media New York 2013
Abstract Prolonged infusion of low-dose gemcitabine and cisplatin (GC) proved to be an effective treatment for patients with advanced bladder cancer. One hundred and twenty untreated patients with stage III/IV bladder cancer were randomized to receive either gemcitabine (250 mg/ m2) 6-h infusion on days 1 and 8, and cisplatin (70 mg/m2) on day 2 every 21-day cycle (arm 1) or gemcitabine (1,250 mg/m2) 30-min infusion on days 1 and 8, with the same dose of cisplatin (arm 2). The 92 males and 28 females included in the study had a median age of 62 years (range 40–85 years). Among the 120 patient, complete response was achieved in 11.7 % (7/60 patients of arm 1) and 5 % (3/60 patients of arm 2). Eighteen patients in arm 1 (30 %) and 17 patients (28.3 %) in arm 2 had partial response on therapy. Thus, the overall response rate of Abstract of this work was presented at ASCO Annual Meeting 2013 as a poster presentation: J Clin Oncol 31, 2013 (suppl; abstr 4537). R. Haggag (&) F. Abu-Taleb Department of Medical Oncology and Hematology, Faculty of Medicine, Zagazig University, Sharkia 44519, Egypt e-mail: [email protected] K. Farag S. Shamaa Oncology Center, Faculty of Medicine, Mansoura University, Mansoura, Egypt A.-R. Zekri Department of Cancer Biology, National Cancer Institute, Cairo University, Cairo, Egypt T. ELBolkainy Department of Pathology, National Cancer Institute, Cairo University, Cairo, Egypt H. Khaled Department of Medical Oncology, National Cancer Institute, Cairo University, Cairo, Egypt
patients in arm 1 and arm 2 was 41.7 % (25/60 patients) and 33.3 % (20/60 patients), respectively (p = 0.37). No significant difference in median time to disease progression (26 vs. 24 months, p = 0.4), median survival (12 vs. 16 months, p = 0.8), and 1-year survival (49.9 vs. 54.7 %, p = 0.8) was detected between arms 1 and 2, respectively. Main toxicities were similar in both arms with no statistically significant differences. Low-dose, prolonged infusion gemcitabine in combination with cisplatin is not inferior to the standard GC regimen with favorable toxicity profile and less financial costs. Keywords Bladder cancer Prolonged infusion Low-dose gemcitabine Cisplatin
Introduction Urothelial bladder cancer (UBC) is the 7th most common cancer in men and the 17th most common in women worldwide. UBC is more common in developed countries and is the fourth and ninth most common cancer in men and women, respectively, in the Western world [1]. An estimated 72,570 new cases of bladder cancer are expected to occur in the United States in 2013 [2]. In Egypt, bladder cancer has been the most common cancer during the past 50 years but with a recent significant decline in its relative frequency [3]. The introduction of combination chemotherapy regimens, such as methotrexate, vinblastine, adriamycin, cisplatin (MVAC) and gemcitabine, cisplatin (GC), has been shown to be useful options for surgically incurable disease [4]. However, gemcitabine and cisplatin combination has clearly demonstrated a similar overall survival with an improved toxicity profile when compared to MVAC [5, 6].
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Gemcitabine is a prodrug that has to be phosphorylated intracellularly to the active metabolites gemcitabine diphosphate and triphosphate [7–9]. The rate of this metabolic conversion is limited by the activity of deoxycytidine kinase. Saturation of deoxycytidine kinase occurs after short infusion at conventional doses leaving most of the drug unmetabolized, while prolonged infusion results in a higher intracellular concentration of the active metabolite, thus enhancing the agent’s efficacy [10]. Efficacy and safety of a combination of cisplatin and low-dose prolonged infusion gemcitabine were tried in our earlier phase II study of 57 untreated patients with advanced bladder cancer and proved to have promising efficacy with tolerable toxicity [11]. This favorable experience encouraged us to compare the efficacy and tolerability of the standard-dose versus the low-dose prolonged infusion gemcitabine and cisplatin for patients with advanced bladder cancer in a randomized phase II study by updating the data and duplicating the number of patients of our preliminary published results [12].
Patients and methods Patients eligible for the trial had histologically proven nonoperable, recurrent, and/or metastatic urinary bladder cancer on top of bilharzial cystitis. Inclusion criteria were: age 18 years or older; Eastern Cooperative Oncology Group performance status (ECOG-PS) B 2; adequate renal, hepatic, and hematologic functions; no previous radiation therapy or chemotherapy; and informed consent. Complete physical examination, routine biochemical laboratories, computed tomography of the abdomen and pelvis, chest X-ray and/or computed tomography, and bone scan according to the site and type of disease were performed to evaluate pretreatment and follow-up tumor measurement and staging. All eligible patients were randomly assigned to chemotherapy with gemcitabine (250 mg/m2 days 1 and 8) administered over 6-h infusion plus cisplatin (70 mg/m2) over 2-h infusion on day 2 of each 21-day cycle (arm 1) or gemcitabine (1,250 mg/m2 days 1 and 8) over half an hour infusion plus cisplatin (70 mg/m2 on day 2) over 2-h infusion of each 21-day cycle (arm 2). All patients were premeditated with appropriate hydration and antiemetics. Patients were considered evaluable for response if they have received at least 2 cycles of chemotherapy. The duration of treatment depended on patient response. Therapy was discontinued after 2 cycles if there was definite disease progression. If patients were responding or had stable disease, two more cycles were given then reevaluation was repeated. Treatment was
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Med Oncol (2014) 31:811 Table 1 Clinico-pathologic characteristics of the 120 bladder cancer patients included in the study Patients parameters
Arm 1
Arm 2
P value
Males (%)
44 (73.3 %)
48 (80 %)
0.39
Females (%)
16 (26.7 %)
12 (20 %)
Median age (range)
60 (40–85)
62 (40–80)
0.48
0.38
ECOG performance status, n (%) 0
1 (1.7 %)
3 (5 %)
1
41 (68.3 %)
44 (73.3 %)
2
18 (30 %)
13 (21.7 %)
Transitional cell carcinoma (%)
42 (70 %)
45 (75 %)
Squamous cell carcinoma (%) Undifferentiated carcinoma (%)
15 (25 %)
13 (21.7 %)
3 (5 %)
2 (3.3 %)
Pathologic type 0.8
Tumor at presentation Primary only
19 (31.7 %)
10 (16.7 %)
Primary with metastasis.
26 (43.3 %)
40 (66.7 %)
Lymph nodes
8
13
Liver
5
9
Bone
3
8
Lung
2
6
Multiple sites
8
4
Metastatic disease after removal of primary tumor
9 (15 %)
4 (6.7 %)
Local recurrence after removal of primary tumor
6 (10 %)
2 (3.3 %)
Metastatic and locally recurrent disease
0 (0 %)
4 (6.7 %)
0.6
Arm 1: Cisplatin and low-dose prolonged infusion gemcitabine Arm 2: Cisplatin and high-dose short infusion gemcitabine
stopped if the disease remained stable for two more cycles while a total of 6 cycles were continued to responding patients. The dose of gemcitabine was reduced to 75 % in the case of moderate neutropenia (range 1.5–2.0 9 109/l) or thrombocytopenia (range 75–100 9 109/l) and omitted if the neutrophils and/or platelets fell below this range. Cisplatin was omitted for creatinine above 1.5 9 UNL. For other non-hematologic toxicities, the drug doses were reduced to 50 % of planned doses or omitted if toxicity grade 3 or 4 has occurred. Assessment of tumor response was carried out after 2, 4, and 6 cycles using the same method as during initial imaging according to RECIST criteria. Side effects of the treatment were assessed according to the NCI Common Toxicity Criteria, version 2.0.
Med Oncol (2014) 31:811
This study was approved by the Institutional Review Board at National Cancer Institute, Cairo University. All the statistics were performed on an ‘‘intent-to-treat population,’’ which was defined as patients who were eligible for the study and were randomized to arm 1 or arm 2. Kaplan–Meier method and log-rank test were used for survival statistics. P values less than or equal 0.05 were considered significant. Statistical analysis was performed using the SPSS software package (version 16.0).
Page 3 of 6 811 Table 2 Toxicity evaluation for the 120 patients who received chemotherapy Toxicity grade
Arm 1
Arm 2
No.
% within arm 1
3
9
15
4
0
P value
No.
% within arm 2
11
23
0.48
17
0.42
7
0.54
10
1.0
2 0
3
1.0
4
6.6
0.68
3.3
1.0
7
1.0
Anemia 3
Neutropenia
Results Patient characteristics
3
4
4
2
10
8 2
Thrombocytopenia 3
3
4
6
15
4 0
Vomiting
Between January 2005 and December 2010, all eligible patients seen at NCI, Cairo University and Medical Oncology and Hematology department, Zagazig University were included in the study. The clinico-pathologic criteria of the 120 patients included in this study are shown in Table 1. They were 92 males and 28 females. Their age ranged between 40 and 85 years (median 62 years). A total of 87 patients had transitional cell carcinoma, 28 had squamous cell carcinoma, and the remaining 5 had undifferentiated carcinoma of the bladder. Of the 120 patients, 95 patients (79 %) had inoperable bladder cancer, 66 of them had metastases in addition (lymph nodes 21, liver 14, bone 11, lung 8, and multiple sites 12 patients). Additional 13 patients had metastases that have developed after surgical removal of primary bladder cancer, while eight patients developed local recurrence only, and four patients presented with both local recurrence and metastases. The clinico-pathologic characteristics of both arms of the study were comparable with no significant differences.
3
6
4
0
10
6 0
Mucositis 3 4
0 0
0
3
2
3.3
4
0
Diarrhea 0
Hepatic (ALT/AST) 3
1
4
0
1.7
2 0
Increased creatinine 3
3
4
0
5
3
1
0
5
Hematuria 3
0.07
DVT 3
2
3.3
2
3.3
1.0
Arm 1: Cisplatin and low-dose prolonged infusion gemcitabine Arm 2: Cisplatin and high-dose short infusion gemcitabine
Dose intensity Among the 120 patients, a total of 408 cycles of chemotherapy (199 cycles in arm 1 and 209 cycles in arm 2) were given with a median number of 3 cycles per patient (range 1–6 cycles). The planned dose intensities for gemcitabine were 167 and 833 mg/m2/w for arm 1 and 2, respectively, while for cisplatin they were 23 mg/m2/w in both arms. The mean received dose intensity for gemcitabine was 142 and 654 mg/m2/w, while for cisplatin it was 20 and 19.5 mg/ m2/week in arm 1 and 2, respectively. So, the relative dose intensity for gemcitabine was 0.84 and 0.83 (p = 0.43) while, for cisplatin it was 0.87 and 0.85 in arm 1 and 2, respectively (p = 0.15).
Toxicity The toxicity pattern was generally tolerable; no toxic deaths occurred among the 120 patients. Grade 3 or 4 hematologic toxicity was: anemia in 15 and 23 % (p = 0.48), neutropenia in 10 and 17 % (p = 0.42), and thrombocytopenia in 15 and 7 % (p = 0.54) for arms 1 and 2, respectively. Febrile neutropenia was observed in two patients in arm 1; these two patients were admitted to hospital and recovered with supportive treatment with no need for growth factors. Non-hematologic toxicities were similar in both arms with no statistically significant differences. Vomiting (grade 3–4) was the most common
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Med Oncol (2014) 31:811
Table 3 Tumor response of the 120 patients
CR
ARM 1 (%) 7 (11.7 )
ARM 2 (%) 3 (5)
PR
18 (30)
17 (28.3)
SD
9 (15)
17 (28.3)
PD
18 (30)
16 (26.7)
Not evaluable
8 (13.3)
Arm Low- Dose Gemcitabine Cisplatin Standard Gemcitabine Cisplatin
1.0
P value 0.8
0.37
7 (11.7)
Arm 1: Cisplatin and low-dose prolonged infusion gemcitabine Arm 2: Cisplatin and high-dose short infusion gemcitabine
observed toxicity represented in 10 % of patients in both arms (Table 2).
Cum Survival
Response
0.6
0.4
0.2
0.0 0
24
48
Response and survival
123
96
Fig. 1 Overall survival of the treated patients in arm 1 and arm 2 (p = 0.8)
Arm
1.0
Low- Dose Gemcitabine Cisplatin Standard Gemcitabine Cisplatin
0.8
Cum Survival
Fifteen patients were not evaluable for response as 14 of them received only 1 cycle and one received 2 cycles. This was due to deterioration of clinical condition (six patients), death due to disease progression (four patients), and refusal to continue treatment or to be evaluated (five patients). Of the 120 patients, complete remission (CR) was achieved in 11.7 % (7/60 patients of arm 1) and 5 % (3/60 patients of arm 2). These remissions were proved radiologically and pathologically. Eighteen patients in arm 1 (30 %) and 17 patients (20.3 %) in arm 2 had partial remission (PR) on therapy. Thus, the overall response rates of patients in arm 1 and arm 2 were 41.7 % (25/60 patients) and 33.3 % (20/60 patients), respectively (p = 0.37; Table 3). Disease stabilization occurred in nine patients (15 %) in arm 1 and 17 patients (28.3 %) in arm 2. Eighteen patients in arm 1 (30 %) and 16 patients in arm 2 (26.7 %) had progressive disease. Eight patients in arm 1 (13.3 %) and 7 patients in arm 2 (11.7 %) did not receive tumor response evaluation. The mean gemcitabine relative dose intensity in responding and non-responding patients was 0.89 ± 0.056 and 0.79 ± 0.099, respectively, for arm 1 (p = 0.001), while for arm 2, it was 0.90 ± 0.04 and 0.76 ± 0.1 for responding and non-responding patients, respectively. Such difference had statistic significance (p = \0.001). All 10 patients who have had CR on chemotherapy chose to undergo radical radiotherapy after chemotherapy. None of them agreed to undergo radical surgery. In arm 1, disease relapsed in four patients after 6, 7, 51, and 79 months, while the other three patients died after 10, 10.7, and 11.3 months due to other causes than disease recurrence, namely cerebrovascular stroke, cardiac problems, and liver cell failure. Two of the three patients, who have had CR in arm 2, are still alive and disease free for 11 and 17 months, while the third patient relapsed after 50 months and died of his disease.
72
OS (month)
0.6
0.4
0.2
0.0 0
12
24
36
48
60
72
84
PFS (month)
Fig. 2 Overall time to disease progression of the treated patients in arm 1 and arm 2 (p = 0.4)
Kaplan–Meier survival estimates were calculated for all the 120 patients after a median follow-up of 9.5 months. For arm 1 patients, the median overall survival duration was 12 months (CI 95 %, 3.8–20.2 months) with 1-year survival rate of 49.9 %, while for arm 2, they were 16 months (CI 95 %, 6.5–25.5 months) and 1-year survival rate was 55 %, respectively (p = 0.8; Fig. 1). Also, the median time to disease progression was 26 months (CI 95 %, 7.6– 44.4 months) for arm 1 and 24 months (CI 95 %, 10.2– 37.8 months) for arm 2 patients (p = 0.4; Fig. 2).
Med Oncol (2014) 31:811
Prognostic factors According to the Memorial Sloan Kettering Risk Index [13], which included 2 risk factors [i.e., Karnofsky performance status less than 80 % and visceral metastases (liver, lung, or bone)], patients were assigned to 3 risk categories depending on the number of presenting unfavorable characteristics. For arm 1, partial or complete remission for patients who had 0, 1, or 2 risk factors was 16 of 20 (80 %), 8 of 24 (33.3 %), and 1 of 8 (12.5 %) patients (p 0.001) and for arm 2, they were 10 of 24 (41.7 %), 10 of 27 (37 %), and 0 of 2 (0 %) patients (p = 0.5), respectively. Median survival times for patients who had 0, 1, or 2 risk factors were 37, 12, 6 (p \ 0.0001), and 26, 9, 4 months (p \ 0.0001), for arm 1 and 2, respectively.
Discussion The burden of cancer in developing countries is growing and will potentially become a problem of critical proportions. It is estimated that by 2020, nearly 60 % of cancer deaths will be in developing countries [14]. So, there is an insistent need for new approaches to improve cancer care in resource-poor countries, as cancer treatment will be restricted because of financial constraints. Bladder cancer is often a disease of the lower social class [15] and still one of the foremost oncologic problems in Egypt. For all these reasons, we compared low-dose gemcitabine in prolonged infusion to the standard chemotherapy of bladder cancer, trying to find a valuable costeffective alternative. This is the first randomized clinical trial to compare the low-dose prolonged versus the standard high-dose short infusion gemcitabine regimens in chemo-naive patients with advanced bladder cancer. So far, no such comparison had been made and all previous results of gemcitabine in prolonged infusion were phase II trials. In this randomized study, the results of low-dose versus standard-dose gemcitabine infusion and cisplatin were noninferior as regarding survival and other efficacy outcome [TDP (p = 0.4), 1-year survival (p = 0.8), and response rates (p = 0.37)]. The results were comparable to our preliminary results [12]. Although the regimen was given over a 6-h infusion rate, it was still given on an outpatient basis. Thus, no additional costs were added. The observed response rates with the low-dose gemcitabine combination arm in our study were comparable to those observed by Khaled et al. [11]. Also, for the standard arm, the response rates were comparable the results of phase II trials using the same gemcitabine–cisplatin
Page 5 of 6 811
combination against advanced carcinoma of the bladder [4, 16–18]. For both arms, toxicity was low, tolerable, with no significant differences between both arms. Both hematologic and non-hematologic toxicity were in agreement with Zwitter et al. [19] who compared standard brief and lowdose prolonged infusion of gemcitabine for advanced nonsmall cell lung cancer but without the occurrence of thrombocytosis, which was common in that trial. In conclusion, despite the pharmacologic rationale for prolonged infusion, this did not translate into greater clinical benefit. But still low-dose prolonged infusion gemcitabine in combination with cisplatin is an effective and well-tolerated regimen for patients with advanced bladder cancer. The good efficacy, mild hematologic toxicity, and lower financial costs make it attractive to those scenarios of lower economic resources. Acknowledgments Prof: Nelly Hassan, NCI, CAIRO University who contributed to and supervised the statistical analysis of the study. Conflict of interest interests.
The authors declare no competing financial
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811 Page 6 of 6 10. Grunewald R, Abbruzzese JL, Tarassoff P, Plunkett W. Saturation of 20 , 20 -difluorodeoxycytidine 50 -triphosphate accumulation by mononuclear cells during a phase I trial of gemcitabine. Cancer Chemother Pharmacol. 1991;27(4):258–62. 11. Khaled H, Emara ME, Gaafar RM, Mansour O, Abdel Warith A, Zaghloul MS, El Malt O. Primary chemotherapy with low-dose prolonged infusion gemcitabine and cisplatin in patients with bladder cancer: a Phase II trial. Urol Oncol. 2008;26(2):133–6. 12. Khaled H, Abu-Taleb F, Haggag R, and Zekri A (2011) Low-dose versus standard-dose gemcitabine infusion and cisplatin for patients with advanced bladder cancer: a randomized phase II trial. J Clin Oncol 29: (suppl 7; abstr 266). 13. Bajorin DF, Dodd PM, Mazumdar M, et al. Long-term survival in metastatic transitional-cell carcinoma and prognostic factors predicting outcome of therapy. J Clin Oncol. 1999;17:3173–81. 14. Lo´pez-Go´mez M, Malmierca E, de Go´rgolas M, Casado E. Cancer in developing countries: The next most preventable pandemic. The global problem of cancer. Crit Rev Oncol Hematol. 2013 Apr 18. pii: S1040-8428(13)00071-1. doi:10. 1016/j.critrevonc.2013.03.011. [Epub ahead of print].
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Med Oncol (2014) 31:811 15. Heinrich J, Mielck A. Social inequality and environmentallyrelated diseases in Germany: review of empirical results. SozPra¨ventivmed. 2000;45:106–18. 16. Khaled HM, Hamza MR, Mansoyr O, et al. A phase II study of gemcitabine plus cisplatin chemotherapy in advanced bilharzial bladder carcinoma. Eur J Cancer. 2000;36(Suppl 2):34–7. 17. Moore MJ, Winquist EW, Murray N. Gemcitabine plus cisplatin, an active regimen in advanced urothelial cancer: a phase II trial if the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 1999;17:2876–81. 18. Kaufman D, Raghavan D, Carducci M. Phase II trial of gemcitabine plus cisplatin in patients with metastatic urothelial cancer. J Clin Oncol. 2000;18:1921–7. 19. Zwitter M, Kovac V, Smrdel U, Vrankar M, Zadnik V. Gemcitabine in brief versus prolonged low-dose infusion, both combined with cisplatin, for advanced non-small cell lung cancer: a randomized phase II clinical trial. J Thorac Oncol. 2009;4(9): 1148–55.
ORIGINAL PAPER
Low-dose versus standard-dose gemcitabine infusion and cisplatin for patients with advanced bladder cancer: a randomized phase II trial—an update Rasha Haggag • Kamel Farag • Fouad Abu-Taleb Sameh Shamaa • Abdel-Rahman Zekri • Tarek ELBolkainy • Hussein Khaled
•
Received: 12 September 2013 / Accepted: 4 December 2013 / Published online: 12 December 2013 Ó Springer Science+Business Media New York 2013
Abstract Prolonged infusion of low-dose gemcitabine and cisplatin (GC) proved to be an effective treatment for patients with advanced bladder cancer. One hundred and twenty untreated patients with stage III/IV bladder cancer were randomized to receive either gemcitabine (250 mg/ m2) 6-h infusion on days 1 and 8, and cisplatin (70 mg/m2) on day 2 every 21-day cycle (arm 1) or gemcitabine (1,250 mg/m2) 30-min infusion on days 1 and 8, with the same dose of cisplatin (arm 2). The 92 males and 28 females included in the study had a median age of 62 years (range 40–85 years). Among the 120 patient, complete response was achieved in 11.7 % (7/60 patients of arm 1) and 5 % (3/60 patients of arm 2). Eighteen patients in arm 1 (30 %) and 17 patients (28.3 %) in arm 2 had partial response on therapy. Thus, the overall response rate of Abstract of this work was presented at ASCO Annual Meeting 2013 as a poster presentation: J Clin Oncol 31, 2013 (suppl; abstr 4537). R. Haggag (&) F. Abu-Taleb Department of Medical Oncology and Hematology, Faculty of Medicine, Zagazig University, Sharkia 44519, Egypt e-mail: [email protected] K. Farag S. Shamaa Oncology Center, Faculty of Medicine, Mansoura University, Mansoura, Egypt A.-R. Zekri Department of Cancer Biology, National Cancer Institute, Cairo University, Cairo, Egypt T. ELBolkainy Department of Pathology, National Cancer Institute, Cairo University, Cairo, Egypt H. Khaled Department of Medical Oncology, National Cancer Institute, Cairo University, Cairo, Egypt
patients in arm 1 and arm 2 was 41.7 % (25/60 patients) and 33.3 % (20/60 patients), respectively (p = 0.37). No significant difference in median time to disease progression (26 vs. 24 months, p = 0.4), median survival (12 vs. 16 months, p = 0.8), and 1-year survival (49.9 vs. 54.7 %, p = 0.8) was detected between arms 1 and 2, respectively. Main toxicities were similar in both arms with no statistically significant differences. Low-dose, prolonged infusion gemcitabine in combination with cisplatin is not inferior to the standard GC regimen with favorable toxicity profile and less financial costs. Keywords Bladder cancer Prolonged infusion Low-dose gemcitabine Cisplatin
Introduction Urothelial bladder cancer (UBC) is the 7th most common cancer in men and the 17th most common in women worldwide. UBC is more common in developed countries and is the fourth and ninth most common cancer in men and women, respectively, in the Western world [1]. An estimated 72,570 new cases of bladder cancer are expected to occur in the United States in 2013 [2]. In Egypt, bladder cancer has been the most common cancer during the past 50 years but with a recent significant decline in its relative frequency [3]. The introduction of combination chemotherapy regimens, such as methotrexate, vinblastine, adriamycin, cisplatin (MVAC) and gemcitabine, cisplatin (GC), has been shown to be useful options for surgically incurable disease [4]. However, gemcitabine and cisplatin combination has clearly demonstrated a similar overall survival with an improved toxicity profile when compared to MVAC [5, 6].
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Gemcitabine is a prodrug that has to be phosphorylated intracellularly to the active metabolites gemcitabine diphosphate and triphosphate [7–9]. The rate of this metabolic conversion is limited by the activity of deoxycytidine kinase. Saturation of deoxycytidine kinase occurs after short infusion at conventional doses leaving most of the drug unmetabolized, while prolonged infusion results in a higher intracellular concentration of the active metabolite, thus enhancing the agent’s efficacy [10]. Efficacy and safety of a combination of cisplatin and low-dose prolonged infusion gemcitabine were tried in our earlier phase II study of 57 untreated patients with advanced bladder cancer and proved to have promising efficacy with tolerable toxicity [11]. This favorable experience encouraged us to compare the efficacy and tolerability of the standard-dose versus the low-dose prolonged infusion gemcitabine and cisplatin for patients with advanced bladder cancer in a randomized phase II study by updating the data and duplicating the number of patients of our preliminary published results [12].
Patients and methods Patients eligible for the trial had histologically proven nonoperable, recurrent, and/or metastatic urinary bladder cancer on top of bilharzial cystitis. Inclusion criteria were: age 18 years or older; Eastern Cooperative Oncology Group performance status (ECOG-PS) B 2; adequate renal, hepatic, and hematologic functions; no previous radiation therapy or chemotherapy; and informed consent. Complete physical examination, routine biochemical laboratories, computed tomography of the abdomen and pelvis, chest X-ray and/or computed tomography, and bone scan according to the site and type of disease were performed to evaluate pretreatment and follow-up tumor measurement and staging. All eligible patients were randomly assigned to chemotherapy with gemcitabine (250 mg/m2 days 1 and 8) administered over 6-h infusion plus cisplatin (70 mg/m2) over 2-h infusion on day 2 of each 21-day cycle (arm 1) or gemcitabine (1,250 mg/m2 days 1 and 8) over half an hour infusion plus cisplatin (70 mg/m2 on day 2) over 2-h infusion of each 21-day cycle (arm 2). All patients were premeditated with appropriate hydration and antiemetics. Patients were considered evaluable for response if they have received at least 2 cycles of chemotherapy. The duration of treatment depended on patient response. Therapy was discontinued after 2 cycles if there was definite disease progression. If patients were responding or had stable disease, two more cycles were given then reevaluation was repeated. Treatment was
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Med Oncol (2014) 31:811 Table 1 Clinico-pathologic characteristics of the 120 bladder cancer patients included in the study Patients parameters
Arm 1
Arm 2
P value
Males (%)
44 (73.3 %)
48 (80 %)
0.39
Females (%)
16 (26.7 %)
12 (20 %)
Median age (range)
60 (40–85)
62 (40–80)
0.48
0.38
ECOG performance status, n (%) 0
1 (1.7 %)
3 (5 %)
1
41 (68.3 %)
44 (73.3 %)
2
18 (30 %)
13 (21.7 %)
Transitional cell carcinoma (%)
42 (70 %)
45 (75 %)
Squamous cell carcinoma (%) Undifferentiated carcinoma (%)
15 (25 %)
13 (21.7 %)
3 (5 %)
2 (3.3 %)
Pathologic type 0.8
Tumor at presentation Primary only
19 (31.7 %)
10 (16.7 %)
Primary with metastasis.
26 (43.3 %)
40 (66.7 %)
Lymph nodes
8
13
Liver
5
9
Bone
3
8
Lung
2
6
Multiple sites
8
4
Metastatic disease after removal of primary tumor
9 (15 %)
4 (6.7 %)
Local recurrence after removal of primary tumor
6 (10 %)
2 (3.3 %)
Metastatic and locally recurrent disease
0 (0 %)
4 (6.7 %)
0.6
Arm 1: Cisplatin and low-dose prolonged infusion gemcitabine Arm 2: Cisplatin and high-dose short infusion gemcitabine
stopped if the disease remained stable for two more cycles while a total of 6 cycles were continued to responding patients. The dose of gemcitabine was reduced to 75 % in the case of moderate neutropenia (range 1.5–2.0 9 109/l) or thrombocytopenia (range 75–100 9 109/l) and omitted if the neutrophils and/or platelets fell below this range. Cisplatin was omitted for creatinine above 1.5 9 UNL. For other non-hematologic toxicities, the drug doses were reduced to 50 % of planned doses or omitted if toxicity grade 3 or 4 has occurred. Assessment of tumor response was carried out after 2, 4, and 6 cycles using the same method as during initial imaging according to RECIST criteria. Side effects of the treatment were assessed according to the NCI Common Toxicity Criteria, version 2.0.
Med Oncol (2014) 31:811
This study was approved by the Institutional Review Board at National Cancer Institute, Cairo University. All the statistics were performed on an ‘‘intent-to-treat population,’’ which was defined as patients who were eligible for the study and were randomized to arm 1 or arm 2. Kaplan–Meier method and log-rank test were used for survival statistics. P values less than or equal 0.05 were considered significant. Statistical analysis was performed using the SPSS software package (version 16.0).
Page 3 of 6 811 Table 2 Toxicity evaluation for the 120 patients who received chemotherapy Toxicity grade
Arm 1
Arm 2
No.
% within arm 1
3
9
15
4
0
P value
No.
% within arm 2
11
23
0.48
17
0.42
7
0.54
10
1.0
2 0
3
1.0
4
6.6
0.68
3.3
1.0
7
1.0
Anemia 3
Neutropenia
Results Patient characteristics
3
4
4
2
10
8 2
Thrombocytopenia 3
3
4
6
15
4 0
Vomiting
Between January 2005 and December 2010, all eligible patients seen at NCI, Cairo University and Medical Oncology and Hematology department, Zagazig University were included in the study. The clinico-pathologic criteria of the 120 patients included in this study are shown in Table 1. They were 92 males and 28 females. Their age ranged between 40 and 85 years (median 62 years). A total of 87 patients had transitional cell carcinoma, 28 had squamous cell carcinoma, and the remaining 5 had undifferentiated carcinoma of the bladder. Of the 120 patients, 95 patients (79 %) had inoperable bladder cancer, 66 of them had metastases in addition (lymph nodes 21, liver 14, bone 11, lung 8, and multiple sites 12 patients). Additional 13 patients had metastases that have developed after surgical removal of primary bladder cancer, while eight patients developed local recurrence only, and four patients presented with both local recurrence and metastases. The clinico-pathologic characteristics of both arms of the study were comparable with no significant differences.
3
6
4
0
10
6 0
Mucositis 3 4
0 0
0
3
2
3.3
4
0
Diarrhea 0
Hepatic (ALT/AST) 3
1
4
0
1.7
2 0
Increased creatinine 3
3
4
0
5
3
1
0
5
Hematuria 3
0.07
DVT 3
2
3.3
2
3.3
1.0
Arm 1: Cisplatin and low-dose prolonged infusion gemcitabine Arm 2: Cisplatin and high-dose short infusion gemcitabine
Dose intensity Among the 120 patients, a total of 408 cycles of chemotherapy (199 cycles in arm 1 and 209 cycles in arm 2) were given with a median number of 3 cycles per patient (range 1–6 cycles). The planned dose intensities for gemcitabine were 167 and 833 mg/m2/w for arm 1 and 2, respectively, while for cisplatin they were 23 mg/m2/w in both arms. The mean received dose intensity for gemcitabine was 142 and 654 mg/m2/w, while for cisplatin it was 20 and 19.5 mg/ m2/week in arm 1 and 2, respectively. So, the relative dose intensity for gemcitabine was 0.84 and 0.83 (p = 0.43) while, for cisplatin it was 0.87 and 0.85 in arm 1 and 2, respectively (p = 0.15).
Toxicity The toxicity pattern was generally tolerable; no toxic deaths occurred among the 120 patients. Grade 3 or 4 hematologic toxicity was: anemia in 15 and 23 % (p = 0.48), neutropenia in 10 and 17 % (p = 0.42), and thrombocytopenia in 15 and 7 % (p = 0.54) for arms 1 and 2, respectively. Febrile neutropenia was observed in two patients in arm 1; these two patients were admitted to hospital and recovered with supportive treatment with no need for growth factors. Non-hematologic toxicities were similar in both arms with no statistically significant differences. Vomiting (grade 3–4) was the most common
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Table 3 Tumor response of the 120 patients
CR
ARM 1 (%) 7 (11.7 )
ARM 2 (%) 3 (5)
PR
18 (30)
17 (28.3)
SD
9 (15)
17 (28.3)
PD
18 (30)
16 (26.7)
Not evaluable
8 (13.3)
Arm Low- Dose Gemcitabine Cisplatin Standard Gemcitabine Cisplatin
1.0
P value 0.8
0.37
7 (11.7)
Arm 1: Cisplatin and low-dose prolonged infusion gemcitabine Arm 2: Cisplatin and high-dose short infusion gemcitabine
observed toxicity represented in 10 % of patients in both arms (Table 2).
Cum Survival
Response
0.6
0.4
0.2
0.0 0
24
48
Response and survival
123
96
Fig. 1 Overall survival of the treated patients in arm 1 and arm 2 (p = 0.8)
Arm
1.0
Low- Dose Gemcitabine Cisplatin Standard Gemcitabine Cisplatin
0.8
Cum Survival
Fifteen patients were not evaluable for response as 14 of them received only 1 cycle and one received 2 cycles. This was due to deterioration of clinical condition (six patients), death due to disease progression (four patients), and refusal to continue treatment or to be evaluated (five patients). Of the 120 patients, complete remission (CR) was achieved in 11.7 % (7/60 patients of arm 1) and 5 % (3/60 patients of arm 2). These remissions were proved radiologically and pathologically. Eighteen patients in arm 1 (30 %) and 17 patients (20.3 %) in arm 2 had partial remission (PR) on therapy. Thus, the overall response rates of patients in arm 1 and arm 2 were 41.7 % (25/60 patients) and 33.3 % (20/60 patients), respectively (p = 0.37; Table 3). Disease stabilization occurred in nine patients (15 %) in arm 1 and 17 patients (28.3 %) in arm 2. Eighteen patients in arm 1 (30 %) and 16 patients in arm 2 (26.7 %) had progressive disease. Eight patients in arm 1 (13.3 %) and 7 patients in arm 2 (11.7 %) did not receive tumor response evaluation. The mean gemcitabine relative dose intensity in responding and non-responding patients was 0.89 ± 0.056 and 0.79 ± 0.099, respectively, for arm 1 (p = 0.001), while for arm 2, it was 0.90 ± 0.04 and 0.76 ± 0.1 for responding and non-responding patients, respectively. Such difference had statistic significance (p = \0.001). All 10 patients who have had CR on chemotherapy chose to undergo radical radiotherapy after chemotherapy. None of them agreed to undergo radical surgery. In arm 1, disease relapsed in four patients after 6, 7, 51, and 79 months, while the other three patients died after 10, 10.7, and 11.3 months due to other causes than disease recurrence, namely cerebrovascular stroke, cardiac problems, and liver cell failure. Two of the three patients, who have had CR in arm 2, are still alive and disease free for 11 and 17 months, while the third patient relapsed after 50 months and died of his disease.
72
OS (month)
0.6
0.4
0.2
0.0 0
12
24
36
48
60
72
84
PFS (month)
Fig. 2 Overall time to disease progression of the treated patients in arm 1 and arm 2 (p = 0.4)
Kaplan–Meier survival estimates were calculated for all the 120 patients after a median follow-up of 9.5 months. For arm 1 patients, the median overall survival duration was 12 months (CI 95 %, 3.8–20.2 months) with 1-year survival rate of 49.9 %, while for arm 2, they were 16 months (CI 95 %, 6.5–25.5 months) and 1-year survival rate was 55 %, respectively (p = 0.8; Fig. 1). Also, the median time to disease progression was 26 months (CI 95 %, 7.6– 44.4 months) for arm 1 and 24 months (CI 95 %, 10.2– 37.8 months) for arm 2 patients (p = 0.4; Fig. 2).
Med Oncol (2014) 31:811
Prognostic factors According to the Memorial Sloan Kettering Risk Index [13], which included 2 risk factors [i.e., Karnofsky performance status less than 80 % and visceral metastases (liver, lung, or bone)], patients were assigned to 3 risk categories depending on the number of presenting unfavorable characteristics. For arm 1, partial or complete remission for patients who had 0, 1, or 2 risk factors was 16 of 20 (80 %), 8 of 24 (33.3 %), and 1 of 8 (12.5 %) patients (p 0.001) and for arm 2, they were 10 of 24 (41.7 %), 10 of 27 (37 %), and 0 of 2 (0 %) patients (p = 0.5), respectively. Median survival times for patients who had 0, 1, or 2 risk factors were 37, 12, 6 (p \ 0.0001), and 26, 9, 4 months (p \ 0.0001), for arm 1 and 2, respectively.
Discussion The burden of cancer in developing countries is growing and will potentially become a problem of critical proportions. It is estimated that by 2020, nearly 60 % of cancer deaths will be in developing countries [14]. So, there is an insistent need for new approaches to improve cancer care in resource-poor countries, as cancer treatment will be restricted because of financial constraints. Bladder cancer is often a disease of the lower social class [15] and still one of the foremost oncologic problems in Egypt. For all these reasons, we compared low-dose gemcitabine in prolonged infusion to the standard chemotherapy of bladder cancer, trying to find a valuable costeffective alternative. This is the first randomized clinical trial to compare the low-dose prolonged versus the standard high-dose short infusion gemcitabine regimens in chemo-naive patients with advanced bladder cancer. So far, no such comparison had been made and all previous results of gemcitabine in prolonged infusion were phase II trials. In this randomized study, the results of low-dose versus standard-dose gemcitabine infusion and cisplatin were noninferior as regarding survival and other efficacy outcome [TDP (p = 0.4), 1-year survival (p = 0.8), and response rates (p = 0.37)]. The results were comparable to our preliminary results [12]. Although the regimen was given over a 6-h infusion rate, it was still given on an outpatient basis. Thus, no additional costs were added. The observed response rates with the low-dose gemcitabine combination arm in our study were comparable to those observed by Khaled et al. [11]. Also, for the standard arm, the response rates were comparable the results of phase II trials using the same gemcitabine–cisplatin
Page 5 of 6 811
combination against advanced carcinoma of the bladder [4, 16–18]. For both arms, toxicity was low, tolerable, with no significant differences between both arms. Both hematologic and non-hematologic toxicity were in agreement with Zwitter et al. [19] who compared standard brief and lowdose prolonged infusion of gemcitabine for advanced nonsmall cell lung cancer but without the occurrence of thrombocytosis, which was common in that trial. In conclusion, despite the pharmacologic rationale for prolonged infusion, this did not translate into greater clinical benefit. But still low-dose prolonged infusion gemcitabine in combination with cisplatin is an effective and well-tolerated regimen for patients with advanced bladder cancer. The good efficacy, mild hematologic toxicity, and lower financial costs make it attractive to those scenarios of lower economic resources. Acknowledgments Prof: Nelly Hassan, NCI, CAIRO University who contributed to and supervised the statistical analysis of the study. Conflict of interest interests.
The authors declare no competing financial
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