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International Journal of Urology (2015) 22, 490–494
doi: 10.1111/iju.12727
Original Article: Clinical Investigation
Maintenance monotherapy with gemcitabine after standard platinumbased chemotherapy in patients with advanced urothelial cancer Satoru Muto,1 Hideyuki Abe,2 Takahiro Noguchi,1 Sho-ichiro Sugiura,1 Kousuke Kitamura,1 Shuji Isotani,1 Hisamitsu Ide,1 Raizo Yamaguchi,1 Takao Kamai2 and Shigeo Horie3 1
Department of Urology, Teikyo University School of Medicine, 3Department of Urology, Juntendo University School of Medicine, Tokyo and 2Department of Urology, Dokkyo Medical University School of Medicine, Tochigi, Japan Abbreviations & Acronyms CBDCA = carboplatin CDDP = cisplatin CKD = chronic kidney disease CTCAE = Common Terminology Criteria of Adverse Events DSS = disease-specific survival GC = gemcitabine and cisplatin GEM = gemcitabine MVAC = methotrexate, vinblastine, adriamycin and cisplatin OS = overall survival PFS = progression-free survival PS = performance status UC = urothelial cancer Correspondence: Satoru Muto M.D., Ph.D., Department of Urology, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo 1738605, Japan. Email: muto@med. teikyo-u.ac.jp Received 12 June 2014; accepted 4 January 2015. Online publication 28 February 2015
Objectives: To investigate the outcomes of gemcitabine maintenance monotherapy treatment for metastatic urothelial cancer. Methods: Gemcitabine maintenance monotherapy was used for metastatic urothelial cancer patients after standard platinum-based chemotherapy. A standard dose of 1000 mg/m2/month was given. If patients suffered adverse events or a noticeably compromised quality of life, treatment intervals were extended and doses lowered. Patients with metastatic urothelial cancer receiving only best supportive care after standard chemotherapy served as the retrospective control group. Results: A total of 33 patients were included in the study group as well as in the control group. Maintenance therapy was administered a median of nine times (range 2–49 times) with a median dose of 984.2 mg (range 500–1400 mg) per time. An adverse event of the Common Terminology Criteria of Adverse Events grade 3 or greater was observed in 10 (30.3%) patients, while nine patients (27.3%) experienced hematotoxicity. After standard chemotherapy pretreatment, disease-specific survival in the maintenance therapy group was an average of 15.0 months, significantly more favorable (P < 0.001) than that of the control group (4.0 months). On multivariate analysis, efficacy of prior chemotherapy (P = 0.018), visceral metastasis (P = 0.007) and gemcitabine maintenance therapy (P < 0.001) were statistically significant prognostic parameters of disease-specific survival. Conclusion: The present study findings suggest that gemcitabine maintenance monotherapy in metastatic urothelial cancer might not only be useful as a palliative treatment, but it could also have a certain level of therapeutic effectiveness.
Key words:
bladder cancer, chemotherapy, gemcitabine, maintenance therapy, metastasis.
Introduction Metastatic UC is known to advance rapidly, often with survival of under 1 year after metastasis to internal distant organs.1 Systemic chemotherapy is standard treatment for metastatic UC, with MVAC and GC regarded as standard first-line chemotherapy.2 Both have favorable response rates, but neither offers a remarkably improved prognosis. The objective, then, is to stabilize the disease with standard chemotherapy.3 The response rate of monotherapy for UC is reported to be 33% with CDDP, 29% with methotrexate, 23% with adriamycin and 5% with paclitaxel; the success rate of GEM is reported to be 29%.4 Taking these results into account, we carried out maintenance monotherapy with GEM after standard platinum-based chemotherapy in patients with advanced UC. The current study investigated the results of that therapy.
Methods Patient characteristics The present study used GEM monotherapy as maintenance after treatment of metastatic UC with standard platinum-based chemotherapy from February 2008 to February 2014 at Teikyo University Hospital, Tokyo, and Dokkyo Medical University Hospital, Tochigi, Japan. Patients who had not undergone radical surgery (radical cystectomy or total nephroureterectomy, for example) were also included in this investigation. Our systemic chemotherapy strategy for metastatic UC was as follows: the standard first-line was MVAC or GC. Patients with renal insufficiency of CKD stage ≥ 2, however, received CBDCA in place of CDDP or decreased doses of CDDP. As 490
© 2015 The Japanese Urological Association
Maintenance GEM monotherapy for UC
second-line, we used any one of MVAC, GC or GEM + CBDCA that was unused as first-line in cases treatable by additional platinum-based chemotherapy. Third-line chemotherapy with GEM + paclitaxel or methotrexate + epirubicin + CDDP was optional and determined by individual patient preference. We initiated GEM monotherapy maintenance with patients whose condition suffered as a result of age, lowered P), or heart, liver, kidney or other organ deterioration causing the attending physician to conclude that further treatment with standard platinum-based first-, second-, or third-line chemotherapy would be difficult. All patients initiating maintenance therapy had cancer metastasis to at least one site. The exclusion criteria for GEM maintenance therapy were low activities of daily living, adverse events of CTCAE grade 3 and above associated with prior chemotherapy, patient’s refusal and inability of regular hospital visit. Patients with other forms of carcinoma, or those who were receiving other chemotherapy, immunotherapy, endocrine therapy or who were involved in other clinical studies were excluded from the present investigation. No patients received any other therapy after GEM maintenance therapy. All patients in the current study granted informed consent after our explanation of the GEM monotherapy as maintenance. The present study utilized the 2009 revision of the TNM classification approved by the International Union against Cancer/American Joint Committee on Cancer to determine the extent of cancer advancement.5 Patients were stratified by Eastern Cooperative Oncology Group performance status.
GEM maintenance monotherapy As a general rule, all patients received a 30-min intravenous administration of GEM on an outpatient basis every 4 weeks. As support therapy, patients received 10 mg of dexamethasone immediately before the administration of GEM. With each cycle, an assessment was made of the patient’s current condition and test data. All patients in the maintenance group received blood and urine tests 1 week after GEM administration to evaluate adverse events. We used version 4 of the CTCAE to identify adverse events. Although 1000 mg/m2 of GEM was administered as the standard dose according to a Japanese multicenter open-label phase II study, we gradually lowered the dose to 500 mg/bodyweight in patients with adverse events of CTCAE grade 3 and above (or those with grade 2 or lower evidencing deteriorating quality of life), and postponed the subsequent dose for up to 1 month.6 GEM maintenance therapy was continued until an unequivocal decline in activities of daily living as a result of cancer progression and/or adverse events, or patient request for discontinuation caused cessation of GEM treatment.
Analysis The present study utilized cases of metastatic UC treated in the Department of Urology, Teikyo University School of Medicine and the Department of Urology, Dokkyo Medical University School of Medicine as a retrospective control for comparison. All patients in the control group had received best supportive care afrer first-, second- or third-line chemotherapy during approximately the same period (from January 2006 to February 2014) in which the GEM group was treated. We observed the © 2015 The Japanese Urological Association
subjective and objective general medical conditions of all patients in both groups every 4 weeks after chemotherapy. Imaging studies including computed tomography and magnetic resonance imaging were carried out every 4 months in the absence of symptoms of tumor recurrence and/or progression. In the present study, progression was defined as either the appearance of any new lesion or a 25% increase in the sum of the products of measurable lesions. Kaplan–Meier standards were used to estimate durations, such as DSS, PFS and OS after pretreatment, cumulative survival curve, median survival and annual survival rate. We used the log–rank test for univariate comparison of variations in the survival rate curve, the odds ratio for intergroup comparison and Pearson’s χ2-test. We used the Cox proportional hazards model to evaluate the therapeutic effect hazard ratio and estimated the DSS value using multivariate analysis with a 95% confidence interval. R 2.14.0 was used to determine the outcome measure.7 A significance level of P < 0.05 was considered to be statistically significant.
Results Patient characteristics Patient demographics are shown in Table 1. We compared a maintenance therapy group of 33 patients with a control group of 33 patients. There was no statistically significant difference (P = 0.057) between the median age of the maintenance therapy group (70.9 ± 8.7) and that of the control group (66.1 ± 8.6). Furthermore, there was no statistically significant difference between the groups in sex (P = 0.398), primary lesion (P = 0.211), PS (P = 0.158), CKD stage (P = 0.142), history or absence of radical surgery (same number) and frequency of metastasis to the lung (P = 0.796), liver (P = 0.800) or bone (same number). Our first- and second-line chemotherapeutic strategy on systemic chemotherapy for metastatic UC was MVAC, GC or GEM + CBDCA. Therefore, all patients in both groups received any one of these regimens. Prior chemotherapy was carried out in patients with both groups in a similar manner. In first-line chemotherapy, there were no significant differences between both groups in the frequency of GC (P = 0.325), MVAC (P = 0.131) and GEM + CBDCA (P = 0.284), respectively. Nor were there any significant differences between the groups (P = 0.284) in the frequency of second- or third-line chemotherapy. The mean number of courses of prior chemotherapy was 2.7 ± 1.5 times in the maintenance group and 2.8 ± 1.6 times in the control group (P = 0.908). There were no significant differences in the efficacy of prior standard chemotherapy between the maintenance and control groups (P = 0.453). The major complications in the maintenance therapy group included other types of carcinoma (five patients, 15.2%), hypertension (10 patients, 30.3%), heart failure (three patients, 9.1%), myocardial infarction (four patients, 12.1%), arrhythmia (two patients, 6.1%) and chronic obstructive pulmonary disease (two patients, 6.1%); in the control group, complications included hypertension (11 patients, 33.3%), diabetes (five patients, 15.2%) and arrhythmia (three patients, 9.1%). After pretreatment, the mean observation period for the maintenance group was 16.8 months, and 10.0 months for the control group (P = 0.133). 491
S MUTO ET AL.
Table 1 Patient characteristics
Sex Male Female Mean age (years) PS 0 1 2 3 CKD stage 0 1 2 3 4 5 Primary site Upper urinary tract Bladder Radical surgery + – Metastatic site Lung Liver Bone Prior chemotherapy First-line GC MVAC GEM + CBDCA Second- or third-line + – Efficacy of prior chemotherapy Progressive disease Stabilize the disease Partial remission Complete remission
Table 2 CTCAE (version 4.0) grade 2 or above adverse events in GEM maintenance therapy Maintenance (n = 33)
Control (n = 33)
P
23 (69.7%) 10 (30.3%) 70.9 ± 8.7
26 (78.8%) 7 (21.2%) 66.1 ± 8.6
0.398
6 (18.2%) 16 (48.5%) 8 (24.2%) 3 (9.1%)
12 (36.4%) 14 (42.4%) 7 (21.2%) 0
0 1 (3.0%) 7 (21.2%) 19 (57.6%) 2 (6.1%) 4 (12.1%)
1 (3.0%) 4 (12.1%) 11 (33.3%) 16 (48.5%) 1 (3.0%) 0
16 (48.5%) 17 (51.5%)
11 (33.3%) 22 (66.7%)
21 (63.6%) 12 (36.4%)
21 (63.6%) 12 (36.4%)
12 (36.4%) 12 (36.4%) 9 (27.3%)
11 (33.3%) 13 (39.4%) 9 (27.3%)
0.796 0.800 –
18 (54.5%) 10 (30.3%) 5 (15.2%)
14 (42.4%) 16 (48.5%) 3 (9.1%)
0.325 0.131 0.451
21 (63.3%) 12 (36.7%)
25 (75.8%) 8 (24.2%)
0.284
5 (15.2%) 25 (75.8%) 1 (3.0%) 2 (6.1%)
9 (27.3%) 19 (57.6%) 1 (3.0%) 4 (12.1%)
0.057
0.158
Hematological Neutropenia Febrile neutropenia Thrombocytopenia Anemia Non-hematological Serum creatinine increased Aspartate aminotransferase increased Alanine aminotransferase increased
Grade 2
Grade 3
Grade 4
2 (6.1%) 0 5 (15.2%) 9 (27.3%)
3 (9.1%) 0 1 (3.0%) 4 (12.1%)
0 0 0 1 (3.0%)
4 (12.1%) 1 (3.0%) 0
0 0 1 (3.0%)
0 0 0
0.142
0.211
toxicity with elevated transaminase (Table 2). Three patients (9.1%) experienced grade 3 neutropenia, but no patient experienced febrile neutropenia of grade 2 or above. One case (3.0%) of grade 3 thrombocytopenia was observed. In terms of renal function, no case of grade 3 or higher creatinine increase was observed.
Oncological effects
0.453
A total of 18 (54.5%) of the 33 maintenance group patients died of cancer, as compared with 24 (72.7%) of the 33 control group patients, a difference that was statistically significant (P = 0.003). Cancer progression was not recognized in 13 patients (39.4%) in the maintenance group. After pretreatment, the median DSS for the maintenance group was 15.0 months, as compared with 4.0 months for the control group (P < 0.001; Fig. 1). The 1- and 2-year DSS rates for the maintenance group were 61.0% (95% CI 43.5–78.5%) and 45.4% (95% CI 26.9–64.0%), respectively, showing favorable statistical significance (P < 0.001) when compared with those for the control group, which were 11.2% (95% CI 0–24.8%). The median time to progression was 12 months in the maintenance group, as compared with 2.0 months for the control group
GEM maintenance monotherapy GEM maintenance therapy was administered a median of nine times (range 2–49 times). A median of 25 days (range 1–206 days) elapsed between the final day of pretreatment and the day on which GEM maintenance therapy commenced. The median one-time GEM dosewas 984.2 mg (range500–1400 mg),with an overall median GEM dose of 7000 mg (range 2800–29 400 mg) during the entire period of maintenance therapy. The median final GEM dose was 800 mg (range 300–1200 mg), with a median initial dose of 1000 mg (range 500–1795 mg), showing a significantly lower final dose (P = 0.003). In 16 (48.4%) of the 33 patients, the dose was lowered over the course of maintenance therapy.
Adverse events Adverse events of CTCAE grade 3 or above were seen in 10 patients (30.3%). Nine patients (27.3%) experienced hematotoxicity and one patient experienced non-hematological 492
Fig. 1 DSS rate per Kaplan–Meier. The mean DSS after completion of pretreatment was 15.0 months for the maintenance therapy group and 4.0 months for the control group (P < 0.001). The 1- and 2-year DSS rates for the maintenance therapy group were 61.0% (95% CI 43.5–78.5%) and 45.4% (95% confidence interval 26.9–64.0%), respectively, significantly favorable when compared with the control group, which was 11.2% (95% CI 0–24.8%; P < 0.001). ( ), maintenance; ( ), control group. © 2015 The Japanese Urological Association
Maintenance GEM monotherapy for UC
Table 3 Univariate using log–rank test and multivariate Cox proportional hazards model to investigate factors influencing DSS Univariate
Primary site (bladder vs upper urinary tract) Prior radical surgery (yes vs no) PS (PS 0 vs ≥1) Visceral metastasis (yes vs no) Previous treatment with GC (yes vs no) Previous treatment with GEM (yes vs no) Previous treatment with MVAC (yes vs no) Efficacy of prior chemotherapy (yes vs no) GEM maintenance therapy (yes vs no)
Multivariate
χ2
P-value
1.203 0.409 1.958 6.279 0.890 0.293 0.092 8.893 15.631
0.273 0.523 0.162 0.012 0.346 0.588 0.762 0.003
International Journal of Urology (2015) 22, 490–494
doi: 10.1111/iju.12727
Original Article: Clinical Investigation
Maintenance monotherapy with gemcitabine after standard platinumbased chemotherapy in patients with advanced urothelial cancer Satoru Muto,1 Hideyuki Abe,2 Takahiro Noguchi,1 Sho-ichiro Sugiura,1 Kousuke Kitamura,1 Shuji Isotani,1 Hisamitsu Ide,1 Raizo Yamaguchi,1 Takao Kamai2 and Shigeo Horie3 1
Department of Urology, Teikyo University School of Medicine, 3Department of Urology, Juntendo University School of Medicine, Tokyo and 2Department of Urology, Dokkyo Medical University School of Medicine, Tochigi, Japan Abbreviations & Acronyms CBDCA = carboplatin CDDP = cisplatin CKD = chronic kidney disease CTCAE = Common Terminology Criteria of Adverse Events DSS = disease-specific survival GC = gemcitabine and cisplatin GEM = gemcitabine MVAC = methotrexate, vinblastine, adriamycin and cisplatin OS = overall survival PFS = progression-free survival PS = performance status UC = urothelial cancer Correspondence: Satoru Muto M.D., Ph.D., Department of Urology, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo 1738605, Japan. Email: muto@med. teikyo-u.ac.jp Received 12 June 2014; accepted 4 January 2015. Online publication 28 February 2015
Objectives: To investigate the outcomes of gemcitabine maintenance monotherapy treatment for metastatic urothelial cancer. Methods: Gemcitabine maintenance monotherapy was used for metastatic urothelial cancer patients after standard platinum-based chemotherapy. A standard dose of 1000 mg/m2/month was given. If patients suffered adverse events or a noticeably compromised quality of life, treatment intervals were extended and doses lowered. Patients with metastatic urothelial cancer receiving only best supportive care after standard chemotherapy served as the retrospective control group. Results: A total of 33 patients were included in the study group as well as in the control group. Maintenance therapy was administered a median of nine times (range 2–49 times) with a median dose of 984.2 mg (range 500–1400 mg) per time. An adverse event of the Common Terminology Criteria of Adverse Events grade 3 or greater was observed in 10 (30.3%) patients, while nine patients (27.3%) experienced hematotoxicity. After standard chemotherapy pretreatment, disease-specific survival in the maintenance therapy group was an average of 15.0 months, significantly more favorable (P < 0.001) than that of the control group (4.0 months). On multivariate analysis, efficacy of prior chemotherapy (P = 0.018), visceral metastasis (P = 0.007) and gemcitabine maintenance therapy (P < 0.001) were statistically significant prognostic parameters of disease-specific survival. Conclusion: The present study findings suggest that gemcitabine maintenance monotherapy in metastatic urothelial cancer might not only be useful as a palliative treatment, but it could also have a certain level of therapeutic effectiveness.
Key words:
bladder cancer, chemotherapy, gemcitabine, maintenance therapy, metastasis.
Introduction Metastatic UC is known to advance rapidly, often with survival of under 1 year after metastasis to internal distant organs.1 Systemic chemotherapy is standard treatment for metastatic UC, with MVAC and GC regarded as standard first-line chemotherapy.2 Both have favorable response rates, but neither offers a remarkably improved prognosis. The objective, then, is to stabilize the disease with standard chemotherapy.3 The response rate of monotherapy for UC is reported to be 33% with CDDP, 29% with methotrexate, 23% with adriamycin and 5% with paclitaxel; the success rate of GEM is reported to be 29%.4 Taking these results into account, we carried out maintenance monotherapy with GEM after standard platinum-based chemotherapy in patients with advanced UC. The current study investigated the results of that therapy.
Methods Patient characteristics The present study used GEM monotherapy as maintenance after treatment of metastatic UC with standard platinum-based chemotherapy from February 2008 to February 2014 at Teikyo University Hospital, Tokyo, and Dokkyo Medical University Hospital, Tochigi, Japan. Patients who had not undergone radical surgery (radical cystectomy or total nephroureterectomy, for example) were also included in this investigation. Our systemic chemotherapy strategy for metastatic UC was as follows: the standard first-line was MVAC or GC. Patients with renal insufficiency of CKD stage ≥ 2, however, received CBDCA in place of CDDP or decreased doses of CDDP. As 490
© 2015 The Japanese Urological Association
Maintenance GEM monotherapy for UC
second-line, we used any one of MVAC, GC or GEM + CBDCA that was unused as first-line in cases treatable by additional platinum-based chemotherapy. Third-line chemotherapy with GEM + paclitaxel or methotrexate + epirubicin + CDDP was optional and determined by individual patient preference. We initiated GEM monotherapy maintenance with patients whose condition suffered as a result of age, lowered P), or heart, liver, kidney or other organ deterioration causing the attending physician to conclude that further treatment with standard platinum-based first-, second-, or third-line chemotherapy would be difficult. All patients initiating maintenance therapy had cancer metastasis to at least one site. The exclusion criteria for GEM maintenance therapy were low activities of daily living, adverse events of CTCAE grade 3 and above associated with prior chemotherapy, patient’s refusal and inability of regular hospital visit. Patients with other forms of carcinoma, or those who were receiving other chemotherapy, immunotherapy, endocrine therapy or who were involved in other clinical studies were excluded from the present investigation. No patients received any other therapy after GEM maintenance therapy. All patients in the current study granted informed consent after our explanation of the GEM monotherapy as maintenance. The present study utilized the 2009 revision of the TNM classification approved by the International Union against Cancer/American Joint Committee on Cancer to determine the extent of cancer advancement.5 Patients were stratified by Eastern Cooperative Oncology Group performance status.
GEM maintenance monotherapy As a general rule, all patients received a 30-min intravenous administration of GEM on an outpatient basis every 4 weeks. As support therapy, patients received 10 mg of dexamethasone immediately before the administration of GEM. With each cycle, an assessment was made of the patient’s current condition and test data. All patients in the maintenance group received blood and urine tests 1 week after GEM administration to evaluate adverse events. We used version 4 of the CTCAE to identify adverse events. Although 1000 mg/m2 of GEM was administered as the standard dose according to a Japanese multicenter open-label phase II study, we gradually lowered the dose to 500 mg/bodyweight in patients with adverse events of CTCAE grade 3 and above (or those with grade 2 or lower evidencing deteriorating quality of life), and postponed the subsequent dose for up to 1 month.6 GEM maintenance therapy was continued until an unequivocal decline in activities of daily living as a result of cancer progression and/or adverse events, or patient request for discontinuation caused cessation of GEM treatment.
Analysis The present study utilized cases of metastatic UC treated in the Department of Urology, Teikyo University School of Medicine and the Department of Urology, Dokkyo Medical University School of Medicine as a retrospective control for comparison. All patients in the control group had received best supportive care afrer first-, second- or third-line chemotherapy during approximately the same period (from January 2006 to February 2014) in which the GEM group was treated. We observed the © 2015 The Japanese Urological Association
subjective and objective general medical conditions of all patients in both groups every 4 weeks after chemotherapy. Imaging studies including computed tomography and magnetic resonance imaging were carried out every 4 months in the absence of symptoms of tumor recurrence and/or progression. In the present study, progression was defined as either the appearance of any new lesion or a 25% increase in the sum of the products of measurable lesions. Kaplan–Meier standards were used to estimate durations, such as DSS, PFS and OS after pretreatment, cumulative survival curve, median survival and annual survival rate. We used the log–rank test for univariate comparison of variations in the survival rate curve, the odds ratio for intergroup comparison and Pearson’s χ2-test. We used the Cox proportional hazards model to evaluate the therapeutic effect hazard ratio and estimated the DSS value using multivariate analysis with a 95% confidence interval. R 2.14.0 was used to determine the outcome measure.7 A significance level of P < 0.05 was considered to be statistically significant.
Results Patient characteristics Patient demographics are shown in Table 1. We compared a maintenance therapy group of 33 patients with a control group of 33 patients. There was no statistically significant difference (P = 0.057) between the median age of the maintenance therapy group (70.9 ± 8.7) and that of the control group (66.1 ± 8.6). Furthermore, there was no statistically significant difference between the groups in sex (P = 0.398), primary lesion (P = 0.211), PS (P = 0.158), CKD stage (P = 0.142), history or absence of radical surgery (same number) and frequency of metastasis to the lung (P = 0.796), liver (P = 0.800) or bone (same number). Our first- and second-line chemotherapeutic strategy on systemic chemotherapy for metastatic UC was MVAC, GC or GEM + CBDCA. Therefore, all patients in both groups received any one of these regimens. Prior chemotherapy was carried out in patients with both groups in a similar manner. In first-line chemotherapy, there were no significant differences between both groups in the frequency of GC (P = 0.325), MVAC (P = 0.131) and GEM + CBDCA (P = 0.284), respectively. Nor were there any significant differences between the groups (P = 0.284) in the frequency of second- or third-line chemotherapy. The mean number of courses of prior chemotherapy was 2.7 ± 1.5 times in the maintenance group and 2.8 ± 1.6 times in the control group (P = 0.908). There were no significant differences in the efficacy of prior standard chemotherapy between the maintenance and control groups (P = 0.453). The major complications in the maintenance therapy group included other types of carcinoma (five patients, 15.2%), hypertension (10 patients, 30.3%), heart failure (three patients, 9.1%), myocardial infarction (four patients, 12.1%), arrhythmia (two patients, 6.1%) and chronic obstructive pulmonary disease (two patients, 6.1%); in the control group, complications included hypertension (11 patients, 33.3%), diabetes (five patients, 15.2%) and arrhythmia (three patients, 9.1%). After pretreatment, the mean observation period for the maintenance group was 16.8 months, and 10.0 months for the control group (P = 0.133). 491
S MUTO ET AL.
Table 1 Patient characteristics
Sex Male Female Mean age (years) PS 0 1 2 3 CKD stage 0 1 2 3 4 5 Primary site Upper urinary tract Bladder Radical surgery + – Metastatic site Lung Liver Bone Prior chemotherapy First-line GC MVAC GEM + CBDCA Second- or third-line + – Efficacy of prior chemotherapy Progressive disease Stabilize the disease Partial remission Complete remission
Table 2 CTCAE (version 4.0) grade 2 or above adverse events in GEM maintenance therapy Maintenance (n = 33)
Control (n = 33)
P
23 (69.7%) 10 (30.3%) 70.9 ± 8.7
26 (78.8%) 7 (21.2%) 66.1 ± 8.6
0.398
6 (18.2%) 16 (48.5%) 8 (24.2%) 3 (9.1%)
12 (36.4%) 14 (42.4%) 7 (21.2%) 0
0 1 (3.0%) 7 (21.2%) 19 (57.6%) 2 (6.1%) 4 (12.1%)
1 (3.0%) 4 (12.1%) 11 (33.3%) 16 (48.5%) 1 (3.0%) 0
16 (48.5%) 17 (51.5%)
11 (33.3%) 22 (66.7%)
21 (63.6%) 12 (36.4%)
21 (63.6%) 12 (36.4%)
12 (36.4%) 12 (36.4%) 9 (27.3%)
11 (33.3%) 13 (39.4%) 9 (27.3%)
0.796 0.800 –
18 (54.5%) 10 (30.3%) 5 (15.2%)
14 (42.4%) 16 (48.5%) 3 (9.1%)
0.325 0.131 0.451
21 (63.3%) 12 (36.7%)
25 (75.8%) 8 (24.2%)
0.284
5 (15.2%) 25 (75.8%) 1 (3.0%) 2 (6.1%)
9 (27.3%) 19 (57.6%) 1 (3.0%) 4 (12.1%)
0.057
0.158
Hematological Neutropenia Febrile neutropenia Thrombocytopenia Anemia Non-hematological Serum creatinine increased Aspartate aminotransferase increased Alanine aminotransferase increased
Grade 2
Grade 3
Grade 4
2 (6.1%) 0 5 (15.2%) 9 (27.3%)
3 (9.1%) 0 1 (3.0%) 4 (12.1%)
0 0 0 1 (3.0%)
4 (12.1%) 1 (3.0%) 0
0 0 1 (3.0%)
0 0 0
0.142
0.211
toxicity with elevated transaminase (Table 2). Three patients (9.1%) experienced grade 3 neutropenia, but no patient experienced febrile neutropenia of grade 2 or above. One case (3.0%) of grade 3 thrombocytopenia was observed. In terms of renal function, no case of grade 3 or higher creatinine increase was observed.
Oncological effects
0.453
A total of 18 (54.5%) of the 33 maintenance group patients died of cancer, as compared with 24 (72.7%) of the 33 control group patients, a difference that was statistically significant (P = 0.003). Cancer progression was not recognized in 13 patients (39.4%) in the maintenance group. After pretreatment, the median DSS for the maintenance group was 15.0 months, as compared with 4.0 months for the control group (P < 0.001; Fig. 1). The 1- and 2-year DSS rates for the maintenance group were 61.0% (95% CI 43.5–78.5%) and 45.4% (95% CI 26.9–64.0%), respectively, showing favorable statistical significance (P < 0.001) when compared with those for the control group, which were 11.2% (95% CI 0–24.8%). The median time to progression was 12 months in the maintenance group, as compared with 2.0 months for the control group
GEM maintenance monotherapy GEM maintenance therapy was administered a median of nine times (range 2–49 times). A median of 25 days (range 1–206 days) elapsed between the final day of pretreatment and the day on which GEM maintenance therapy commenced. The median one-time GEM dosewas 984.2 mg (range500–1400 mg),with an overall median GEM dose of 7000 mg (range 2800–29 400 mg) during the entire period of maintenance therapy. The median final GEM dose was 800 mg (range 300–1200 mg), with a median initial dose of 1000 mg (range 500–1795 mg), showing a significantly lower final dose (P = 0.003). In 16 (48.4%) of the 33 patients, the dose was lowered over the course of maintenance therapy.
Adverse events Adverse events of CTCAE grade 3 or above were seen in 10 patients (30.3%). Nine patients (27.3%) experienced hematotoxicity and one patient experienced non-hematological 492
Fig. 1 DSS rate per Kaplan–Meier. The mean DSS after completion of pretreatment was 15.0 months for the maintenance therapy group and 4.0 months for the control group (P < 0.001). The 1- and 2-year DSS rates for the maintenance therapy group were 61.0% (95% CI 43.5–78.5%) and 45.4% (95% confidence interval 26.9–64.0%), respectively, significantly favorable when compared with the control group, which was 11.2% (95% CI 0–24.8%; P < 0.001). ( ), maintenance; ( ), control group. © 2015 The Japanese Urological Association
Maintenance GEM monotherapy for UC
Table 3 Univariate using log–rank test and multivariate Cox proportional hazards model to investigate factors influencing DSS Univariate
Primary site (bladder vs upper urinary tract) Prior radical surgery (yes vs no) PS (PS 0 vs ≥1) Visceral metastasis (yes vs no) Previous treatment with GC (yes vs no) Previous treatment with GEM (yes vs no) Previous treatment with MVAC (yes vs no) Efficacy of prior chemotherapy (yes vs no) GEM maintenance therapy (yes vs no)
Multivariate
χ2
P-value
1.203 0.409 1.958 6.279 0.890 0.293 0.092 8.893 15.631
0.273 0.523 0.162 0.012 0.346 0.588 0.762 0.003
