Renal and urothelial cancers

Different clinicopathological features between patients who developed early and late recurrence following surgery for renal cell carcinoma

Author(s)：: Yoichi Fujii, Masaomi Ikeda, Mariko Tabata, Kazuhiro Kurosawa, Takayuki Kamigaito, Chihiro Hosoda, Toshikazu Okaneya
Affiliation(s)：: Tranomon Hospital

INTRODUCTION AND OBJECTIVE: Radical or partial nephrectomy is the gold standard approach for patients with localized renal cell carcinoma (RCC). However, 20 to 40% of patients tend to develop disease recurrence after adequately performed nephrectomy. While most recurrences of RCC occur within 5 years, up to 10% of them develop beyond 5 years following curative surgery. Although late recurrence is well known these days among urologists as one of the specific biological behaviours of RCC, little is known about it. The aims of this study were to evaluate the clinicopathological features and show the predictive factors of the patients with early or late recurrence following initial curative surgery for localized RCC.

MATERIAL AND METHODS: From April 1988 to January 2013, a total of 504 patients with RCC had undergone either radical nephrectomy or partial nephrectomy. Eighteen patients with synchronous metastases at the initial diagnosis were excluded from this study. Recurrence within 5 years and more than 5 years after surgery was defined as early and late recurrence, respectively. Multivariate logistic regression analysis was applied to define clinical and pathological factors (age at initial surgery, gender, clinical symptoms, performance status, pathological T stage, lymph node metastasis, tumor grade, lymphovascular invasion [LVI], histological subtype) correlated to early and late recurrence following primary surgical treatment. Cancer-specific survival (CSS) analysis after recurrence was performed using the Kaplan-Meier method.

RESULTS: Of the 486 patients, 391 (80.5%) patients developed no recurrence, although 77 (15.8%) and 18 (3.7%) patients developed early and late recurrence, respectively. The median age at initial surgery of early and late recurrence group was 62.0 years and 68.0 years, respectively (P = 0.097). The median follow-up duration was 48.4 months and 105.9 months, respectively (P < 0.0001). In early recurrence group, the number of patients in each pathological stage were 15 in　pT1, 13 in pT2, 39 in pT3 and 10 in pT4. In contrast, in late recurrence group, the number of patients were 8 in pT1, 5 in pT2, 5 in pT3 and 0 in pT4. Patients who developed early recurrence were more likely to have higher T stage, higher tumor grade, positive LVI and clinical symptoms at diagnosis. Multivariate logistic regression analysis showed that positive symptom, ≥pT2 stage, LVI(+) and tumor grade 3 were independent predictive factors for early recurrence. On the other hand, age at surgery and ≥pT2 stage were significantly correlated to late recurrence. The 5-year CSS rate after recurrence was 72.4% in the late recurrence group and 52.9% in the early recurrence group, respectively (P = 0.044).

CONCLUSIONS: The risk factors of clinical recurrence were different according to the duration from initial surgery to the diagnosis of metastasis in patients with localized RCC. Our study showed age and pT stage at initial surgery were the predictive factors of late recurrence. Further investigation obtained from much more patients stratified by clinical stage etc. will be required to clearly predict which patients may develop recurrence in future and to choose adequate treatment.

Prognostic classification of clear cell renal cell carcinoma by gene expression
profiling using DNA microarray

Author(s)：: Tomohiko Yanagida, Kei Ishibashi, Hidenori Akaihata, Ken Kumagai, Nobuhiro Haga, Nobuhiro Kushida, Ken Aikawa, Yoshiyuki Kojima.
Affiliation(s)：: Department of Urology, Fukushima Medical University School of Medicine

Introduction and Objective: Several sets of genes that might predict the prognosis of clear cell renal cell carcinoma (ccRCC) obtained from gene expression profiling using DNA microarrays have been reported. The objective of this study is to identify prognostic classification of ccRCC by DNA microarray using non-amplified RNA samples. Materials and Methods: This study was included consecutive 52 patients of stage I-IV ccRCC who underwent nephrectomy at our institution from 2008 to 2012．Total RNA was extracted from snap-frozen samples of 52 primary ccRCC tumors and 32 normal renal cortex tissues. Poly(A)+ RNA was isolated from total RNA. Then, DNA microarray was done using these non-amplified RNA samples. Results: In cluster analysis, all samples were separated into two distinct clusters, ccRCC and normal renal cortex samples. Furthermore, ccRCC samples were separated into two distinct clusters. We identified 31 transcripts that can be distinguished to the similar prognostic classification of ccRCC. Kaplan-Meier analysis demonstrated that significant difference in cancer-specific survival between these two sub-groups of ccRCC (p<0.001). Multivariate analysis showed that classification of 31 transcripts were independent predictors of cancer-specific suvival of ccRCC patients. Our unique 31 transcript set was different from the several prognostic gene sets that have been previously reported. Conclusions: Our results suggest that there are at least two distinct molecular subtypes showing the different prognosis in ccRCC. Our unique transcript set has the potential to be distinguished poor-prognosis patient from clinical ccRCC patients.

Intravesical seeding of upper urinary tract urothelial carcinoma cells

Author(s)：: Akihiro Ito ^1,4, Ichiro Shintaku ^2,4, Makoto Satoh ^3,4, Shinichi Yamashita ^1,4,
Yoichi Arai ^1,4
Affiliation(s)：: ¹Dept. of Urology, Tohoku Univ. School of medicine, ²Dept. of Urology, Senseki Hospital, ³Dept. of Urology, Sen-en Rifu Hospital, ⁴on behalf of the Tohoku Urological EBM Study Group

Purpose:THPMG trial (The Pirarubicin (THP) Monotherapy Study Group trial) was a randomized phase II study to evaluate the efficacy of a single intravesical instillation of THP for prevention of bladder recurrence after nephroureterectomy for upper urinary tract urothelial carcinoma (UUT-UC). This study conducted further analysis of the THPMG cohort, focusing on intravesical seeding of cancer cells from upper urinary tract.
Patients and Methods: From December 2005 to November 2008, 77 patients clinically diagnosed with UUT-UC from 11 institutions participating in the Tohoku Urological EBM Study Group were pre-operatively enrolled in this study. Patients were randomly assigned to receive or not receive a single instillation of THP (30 mg in 30 ml saline) into the bladder within 48 hours following nephroureterectomy. Cystoscopy and urinary cytology were repeated every 3 months for 2 years or until the occurrence of first bladder recurrence. Using the data from this THPMG trial, bladder recurrence-free survival rate and factors associated with bladder recurrence in the control group were analyzed.
Results: Of 36 patients in the control group, 14 patients with positive urine cytology had more frequent recurrence when compared with the 22 patients with negative urine cytology (p=0.004). Based on multivariate analysis in the control group, voided urine cytology was an independently predictive factor of bladder recurrence (HR, 5.54; 95% confidence interval [CI], 1.12-27.5; p=0.036).
Of 72 patients in the THPMG trial, 31 had positive urine cytology. Among these 31 patients, 17 patients who received THP instillation had fewer recurrences when compared with 14 patients who received control treatment (p = 0.0001). On multivariate analysis, THP instillation was an independent predictor of better recurrence-free survival rates in the patients with positive urine cytology (HR, 0.02; 95% CI, 0.00-0.53; p=0.018). Of 21 patients who had a subsequent bladder recurrence, 17 had recurrent tumor around cystotomy or in the bladder neck compromised by the urethral catheter, supporting the notion that tumor cells seeded in the injured urothelium.
Conclusions: Intravesical instillation of THP immediately after surgery significantly reduced the bladder recurrence rate of patients with positive voided urine cytology. These results suggest that intravesical seeding of UUT-UC occurs during nephroureterectomy. A phase III, large-scale, multicenter study is needed to confirm the therapeutic efficacy of THP instillation and to clarify the mechanism of intravesical seeding from UUT-UC.

Gemcitabine-docetaxel-carboplatin as second-line chemotherapy in patients with advanced urothelial carcinoma for whom gemcitabine-cisplatin chemotherapy has failed

Author(s)：: Akitoshi Fukatsu*1, Osamu Kamihira*1, Kyosuke Kimura*2, Tsuyoki Hirabayashi*1, Asaomi Yamaguchi*1, Hiroki Hirabayashi*1 Yoshie Moriya*1, Yoko Yoshikawa*1, Osamu Matsuura*1
Affiliation(s)：: Department of Urology, Komaki City Hospital*1
Department of Urology, National Hospital Organization Nagoya Medical Center*2

Introduction and Objective
Recently, gemcitabine-cisplatin (GC) chemotherapy has become a standard treatment for patients with advanced urothelial carcinoma (UC). However, there is no standard follow-up treatment for cases where GC is unsuccessful. This study evaluated the efficacy and toxicity of gemcitabine-docetaxel-carboplatin (GDC) as a second-line chemotherapy.

Materials and Methods
From February 2009 to December 2012, 151 patients with advanced UC received GC as first-line chemotherapy. Twenty-five patients who received GDC as second-line chemotherapy after GC had failed were enrolled in this study. 750 mg/m2 of gemcitabine (days 1 & 8), 50 mg/m2 of docetaxel (day 1), and carboplatin (AUC 5) (day 1) were administered in 21-day cycles. The median of cycles was 3 (range 1-6). Treatment was ceased when evidence of relapse was found or when the side-effects became extreme.

Results
A total of 25 patients (23 men and 2 women, with a median age of 69.3 years) were treated. The median follow up duration was 8.2 months (range 1.9-18.5). The results were that 13 of the patients (52%) showed a partial response to the treatment, but none showed a complete response. Median progression-free and overall survival periods were 6.7 and 12.9 months, respectively. The 1-year progression-free and overall survival rates were 39.5% and 55.6%, respectively. After GDC as second-line chemotherapy, the patients who showed no response to GC as first-line chemotherapy survived significantly longer than those who showed a response. The patients who showed a response to GDC as second-line chemotherapy survived significantly longer than those who showed no response. Grade 3 or 4 toxicity was observed in 18 patients (72%), including neutropenia (36%), anemia (24%) and thrombocytopenia (60%), anorexia (28%), nausea/vomiting (24%), diarrhea (16%).

Conclusion
GDC chemotherapy was found to be effective even in some patients with GC-resistant UC, and the toxicity was manageable. The authors therefore conclude that GDC chemotherapy could be an optional treatment for patients with advanced UC in cases where GC chemotherapy has failed.

Therapeutic drug monitoring of sunitinib for patients with renal cell carcinoma

Author(s)：: Satoshi Noda¹, Takashi Otsuji², Toshihiko Yoshioka², Hiroto Yamashita³, Tetsuya Yoshida³, Susumu Kageyama³, Keisei Okamoto³, Yusaku Okada³, Hiroyuki Onishi⁴, Daiki Hira¹, Shin-ya Morita¹, Tomohiro Terada¹
Affiliation(s)：: ¹Department of Pharmacy, Shiga Univ. of Medical Science Hospital
²Department of Pharmacy, Shiga Medical Center for Adults
³Department of Urology, Shiga Univ. of Medical Science Hospital
⁴Department of Urology, Shiga Medical Center for Adults

Purpose Sunitinib has been approved for the treatment of advanced and/or metastatic renal cell carcinoma (RCC). Patients treated with sunitinib frequently require dose reduction and discontinuation due to its severe toxicities. It was reported that sunitinib inhibits VEGFR-2 and PDGF-β phosphorylation in tumor-bearing mice at a total concentration of sunitinib (sunitinib and SU12662) of 50 to 100 ng/ml. Previous studies also demonstrated that most patients with total sunitinib trough concentration ≥100 ng/mL showed dose-limiting toxicity in western countries. However, there is little information for Japanese patients, focusing on pharmacokinetic approaches to evaluate side effects of sunitinib. To explore the optimal concentration of sunitinib, we evaluate the association of the pharmacokinetics (PK) of sunitinib with its toxicities and time to treatment failure (TTF) in Japanese patients with RCC.
Patients and methods Twenty-one RCC patients treated with sunitinib were enrolled between September 2010 and March 2013. Enrolled patients were followed up at Shiga University of Medical Science Hospital and Shiga Medical Center for Adults. This study was approved by the relevant institutional review boards. Sunitinib was treated with at a dose of 50 mg, 37.5 mg, or 25 mg daily based on the treating physicians' recommendation for 4 weeks of a 6-week cycle for the first cycle. Subsequently, doses reductions or drug discontinuations were adjusted based on adverse events by the treating physician. After obtaining informed consents from the patients, blood samples were collected just before administration on a steady state after initiation of sunitinib treatment. Sunitinib and SU12662 were measured by high-performance liquid chromatography. Toxicities during the treatment were graded according to Common Toxicity Criteria for Adverse Effect v4.0.
Results The mean daily dose of sunitinib for the first cycle was 41.1±10.6 mg. The mean total sunitinib concentration was 97.1±36.8 ng/mL. The median duration of treatment was 212 days (range 11-781). Good inverse correlation was found between total sunitinib concentration and the blood plate count (r=－0.48), but not the hemoglobin level (r=0.03) and leukocyte count (r=0.19). Total sunitinib concentration was significantly higher in patients experienced with anorexia, fatigue and bleeding event. Beside, total sunitinib concentration was not correlated with other adverse events such as hand-foot syndrome and hypertension. The patients with a total sunitinib concentration of less than 100 ng/mL (n=13) have a significantly longer of TTF than that of more than 100 ng/mL (n=8) (686 days vs. 71 days, P<0.05).
Conclusion The present study showed that several side effects of sunitinib were dose-dependent. Discontinuation occurred significantly more frequent in patients with total sunitinib trough concentrations > 100 ng/mL. Dose reduction may be needed, especially when a steady-state total sunitinib concentration was above 100 ng/mL. These findings suggest that therapeutic drug monitoring of sunitinib could be helpful for avoiding sever side effect, resulting in prolonged TTF on sunitinib therapy. However, due to small number of patients, further PK research is required.

Efficacy of high-slip skin care pad on sorafenib-induced hand-foot skin reaction

Author(s)：: Nobuo Shinohara¹⁾, Norio Nonomura²⁾, Go Kimura³⁾, Masatoshi Eto⁴⁾, Hironobu Minami⁵⁾, Naoya Yamazaki⁶⁾, Shouji Tokunaga⁷⁾, Seiji Naito⁸⁾, Japanese Society of Renal Cancer
Affiliation(s)：: ¹⁾Department of Renal and Genitourinary Surgery, Hokkaido university, Hokkaido, Japan
²⁾Department of Urology, Osaka University, Graduate School of Medicine, Suita, Japan
³⁾Department of Urology, Nippon Medical School, Tokyo, Japan
⁴⁾Department of Urology, Faculty of Life Science, Kumamoto University, Kumamoto, Japan
⁵⁾Division of Medical Oncology/Hematology, Kobe University Hospital, Kobe, Japan
⁶⁾Dermatology Division, National Cancer Center Hospital, Tokyo, Japan
⁷⁾Medical Information Center, Kyushu University Hospital, Fukuoka, Japan
⁸⁾Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

Background: Hand-foot skin reaction (HFSR) is the most clinically significant and dose-limiting dermatologic toxicity in patients with metastatic renal cell carcinoma who receive sorafenib. At present, evidence-based management strategy is not completely established. Since HFSR may be attributed to keratinous disorders of the skin and tends to develop in particular in areas on the soles of the feet subject to strong pressure, a high-slip skin care pad (hydrocolloid dressing containing ceramide; Remois pad^® ALCARE Co. Ltd., Tokyo, Japan), which is a protective dressing against pressure ulcer, may prevent the development and worsening of sorafenib associated HFSR. The purpose of the study is to investigate the usefulness of high-slip skin care pad for HFSR on the soles of the feet.

Methods: Patients with grade 1 HFSR on the soles developed in metastatic renal cell carcinoma patients treated with sorafenib were randomly assigned 1:1 to receive a high-slip skin care pad (Arm A) or 10% urea cream (Arm B). Sorafenib was administered 800mg daily. A high-slip skin care pad was applied to the affected sites on the soles of the feet every 2-3 days, but not to the hands. A 10% urea cream was ordered to apply and rub to affected sites 2 or 3 times per day. Their subsequent progress was monitored every two weeks. The primary endpoint was the incidence of Grade 2 or 3 HFSR on the soles during 4 weeks after the initiation of management. The secondary endpoints were the time until the occurrence of Grade 2 or more HFSR on the soles, the relative dose intensity (RDI) of sorafenib, QOL assessment, and adverse events.

Results: A total of 33 patients were evaluated; 17 patients in Arm A and 16 patients in Arm B. There were no significant differences in baseline characteristics between two arms. Over the 4 weeks period of this study, the incidence of Grade 2 or 3 HFSR on the soles was significantly lower in Arm A than Arm B; 5 (29%) patients in Arm A versus 11 (69%) patients in Arm B [p=0.03]. On the other hand, the incidence of HFSR on the hands was similar between two arms. The median time to Grade 2 or 3 HFSR on the soles was significant longer in Arm A compared with Arm B; not reach (95%CI 13-28+) in Arm A versus 22 days (95%CI 15-27) [p=0.03]. The relative dose intensity of sorafenib was 82 ± 27 % in Arm A and 73 ± 26 % in Arm B. No significant difference was observed between the 2 groups (P=0.358). The mean pain score during the last 7 days at 4 weeks after initiation of management was lower in Arm A than in Arm B (P=0.05). Regarding adverse events, a mild skin sore was noted in 1 patient in Arm A, but no adverse event was observed in Arm B.

Conclusions: These results revealed that a high-slip skin care pad was effective for controlling HFSR in metastatic renal cell carcinoma patients who received sorafenib. The present study is the first attempt to statistically demonstrate the effectiveness of the dressing in the management of HFSR and is considered to provide evidence-based management.

Randomized phase III trial of neoadjuvant chemotherapy with methotrexate, doxorubicin, vinblastine
and cisplatin (MVAC) followed by radical cystectomy compared with RC alone for muscle-invasive bladder
cancer : Japan Clinical Oncology Group study, JCOG0209

Author(s)：: Kiyohide Fujimoto¹, Hiroshi Kitamura², Taiji Tsukamoto², Naoya Masumori², Taro Shibata³, Hiroyuki Fujimoto⁴, Yoshihiko Hirao¹, Yasuo Kitamura⁵, Yoshihiko Tomita⁶, Ken-ichi Tobisu⁷, Masashi Niwakawa⁷, Seiji Naito⁸, Masatoshi Eto⁹, Yoshiyuki Kakehi¹⁰
Affiliation(s)：: ¹Department of Urology, Nara Medical University, Nara
²Department of Urology, Sapporo Medical University School of Medicine, Hokkaido
³Japan Clinical Oncology Group Data Center/Operations Office, Multi-institutional Clinical Trial Support Center, National Cancer Center, Tokyo
⁴Department of Urology, National Cancer Center Hospital, Tokyo
⁵Department of Urology, Niigata Cancer Center Hospital, Niigata
⁶Department of Urology, Yamagata University Faculty of Medicine, Yamagata
⁷Department of Urology, Shizuoka Cancer Center, Shizuoka
⁸Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka
⁹Department of Urology, Faculty of Life Sciences, Kumamoto University, Kumamoto
¹⁰Department of Urology, Kagawa University Faculty of Medicine, Kagawa

Background: Although several early studies failed to prove the survival benefit of neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC), meta-analyses concluded that cisplatin-based NAC for patients with muscle-invasive bladder cancer (MIBC) had a 5–8% overall survival (OS) advantage.
Purpose: To determine the potential benefit of NAC on OS, we conducted a randomized phase III trial for patients who were candidate for RC with cT2-TaN0M0 bladder cancer.
Methods: Eligibility criteria included histologically proven urothelial carcinoma, MIBC (T2-4aN0M0) within 8 weeks from transurethral resection of bladder tumor, Eastern Cooperative Oncology Group performance status 0-1, and age 20-75 years. Patients were randomized to receive 2 cycles of neoadjuvant chemotherapy with the combination of methotrexate, doxorubicin, vinblastine and cisplatin (MVAC) followed by RC (NAC arm) or RC alone (RC arm). The primary endpoint was OS. Secondary endpoints were progression-free survival (PFS), surgery-related complications, adverse events during NAC, the percent with no residual tumor in the RC specimens (pT0), and QOL. The sample size was 180 patients in each arm with a one-sided alpha of 5% and a power of 80% to detect a difference in 5-year OS from 45% in the RC arm to 57% in the NAC arm.
Results: From March 2003 to March 2009, 130 patients were randomly allocated to the NAC arm (n=64) and RC arm (n=66). Fifty-nine patients in the NAC arm and 65 in the RC arm underwent radical cystectomy. The patient registration was terminated earlier than the schedule because of slow accrual. At the second interim analysis conducted after the completion of patient accrual, the 5-year OS rate of the NAC arm was 72.3% (59.2%-81.9%) and that of the RC arm was 62.4% (49.0%-73.2%). The OS of the NAC arm was better than that of the RC arm, although the difference was not statistically significant (HR, 0.65; multiplicity adjusted 99.99%CI, 0.19-2.18; one-sided log-rank p = 0.07).
Considering the current situation in which NAC with gemcitabine and cisplatin (GC) is widely used in clinical practice, the Data and Safety Monitoring Committee recommended early publication of the results. The 5-year PFS of the NAC arm was 69.1% (55.8%-79.1%) and that of the RC arm was 56.4% (43.2%-67.7%). The PFS of the NAC arm was better than that of the RC arm (HR, 0.61; 95% CI, 0.35-1.06, one-sided log-rank p=0.04). No remarkable difference was observed in operation time, estimated blood loss, transfusion rate, and the number of lymph nodes removed between the NAC and RC arms. No remarkable differences in perioperative complications, other than lymph leakage (NAC arm 1.7% vs. RC arm 12.3%, p=0.035) and anastomotic leak (NAC arm 12.1% vs. RC arm 1.5%, p=0.0257) were observed between the NAC and RC arms. Late postoperative complications with hydronephrosis, renal dysfunction, and abdominal incision hernia showed no significant differences between the arms. In the NAC arm with MVAC, the percent with G3-G4 adverse event of neutropenia, appetite loss, nausea, febrile neutropenia, and anemia was 87.3% 28.6%21.4%, 17.9%, and 14.3%, respectively. In the pathological outcomes of NAC and RC arms, 34.4% and 9.4% of the patients had pT0, respectively (p=0.0011).
Conclusions: Although NAC with GC is widely used for MIBC, NAC with MVAC can still be considered promising since 2 cycles of NAC provided a significant increase of the percent pT0 and favorable PFS and OS.

Galectin 9 and PINCH, novel immunotherapy targets of renal cell carcinoma

Author(s)：: Hidenori Kawashima, Satoshi Tamada, Taro Iguchi, Junji Uchida, Katsuyuki Kuratsukuri, Tomoaki Tanaka, Tatsuya Nakatani
Affiliation(s)：: Department of Urology, Osaka City University Graduate School of Medicine

On the postulation that remarkable responders to cytokine therapies had specific cellular immunity against renal cell carcinoma (RCC), with antibodies that reacted to cancer antigens, we analyzed and then generalized mechanisms by which partial or complete response was achieved among a limited number of patients with metastatic RCC treated with interferon or interleukin-2. In order to isolate tumor antigens actually involved in cancer immunity against RCC, we screened an expression library of RCC (clear cell carcinoma) using as probes the sera of patients with metastatic RCC who showed partial or complete response to cytokine therapy. We obtained 15 different genes related to T-cell death, inhibition of tumor suppressors, mitosis, ubiquitin-proteasome system, chromatin remodeling, epithelial-mesenchymal transition etc. Among them, two novel genes, galectin 9 and PINCH, were much more highly expressed in cancerous lesions than in normal tissues in all patients with clear cell carcinoma in our study (18/18). Peripheral blood mononuclear cells (PBMCs) from healthy volunteers were then stimulated with antigen-derived peptides to induce specific cytotoxic T lymphocytes (CTLs). Specific CTL activities were measured by 51Cr-releasing assay. Both HLA-A*2402- and HLA-A*0201-restricted CTLs were induced by each antigen-derived peptide to show specific and highly cytotoxic anti-RCC activities. Flow cytometry analysis of CTLs labeled with FITC anti-CD107a and APC anti-CD8 showed abundant induction of specific CTLs. Clonal expansion of CTLs was shown by clonality of TCR-Vβ repertoires. This novel approach yielded promising tumor antigens as immunotherapy targets for RCC.

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