Med Oncol (2014) 31:912 DOI 10.1007/s12032-014-0912-9
ORIGINAL PAPER
Organ preservation for muscle-invasive bladder cancer by preoperative intra-arterial chemotherapy and transurethral resection Bangmin Han • Shengjie Liang • Yifeng Jing • Di Cui • Xiao An • Qingsong Zou • Haibin Wei Shujie Xia
•
Received: 14 January 2014 / Accepted: 4 March 2014 / Published online: 14 March 2014 Ó Springer Science+Business Media New York 2014
Abstract The aim of this study was to evaluate the clinical outcomes achieved by use of preoperative intraarterial chemotherapy and transurethral resection of bladder tumors as bladder preservation therapy in treatment of muscle-invasive bladder cancer. Patients with clinical stage T2-T4aN0M0 muscle-invasive bladder cancer were treated with 3 courses of preoperative cisplatin-based intra-arterial chemotherapy at 4-week intervals. Following treatment, the tumors were completely removed by transurethral resection, and all patients received epirubicin for intravesical instillation as a maintenance strategy. Patients showing a complete response received continuous monitoring, and radical cystectomy was strongly recommended for patients who did not achieve a complete response. Between August 2005 and October 2012, a total of 127 patients completed treatment with a bladder preservation therapy, and the median follow-up time for all patients was 31.9 months (range 5–87 months). Among these patients, 91 (71.7 %) achieved a complete response, and the 5-year overall survival and disease-specific survival rates for all patients were 50.2 and 59.5 %, respectively. Among the patients who demonstrated a complete response, 10 experienced a superficial relapse and 15 experienced an invasive cancer relapse. The 5-year recurrence-free and
B. Han S. Liang Y. Jing D. Cui Q. Zou H. Wei S. Xia (&) Department of Urology, Shanghai First People’s Hospital Affiliated to Shanghai Jiaotong University, No. 100, Haining Road, Shanghai 200080, China e-mail: [email protected]; [email protected] X. An Department of Vascular Surgery and Interventional Radiology, Shanghai First People’s Hospital Affiliated to Shanghai Jiaotong University, No. 100, Haining Road, Shanghai 200080, China
progression-free survival rates were 62.2 and 76.9 %, respectively. An analysis of tumor-related factors suggested that clinical stage was significant for predicting both complete response and overall survival. These results suggest that preoperative intra-arterial chemotherapy combined with transurethral resection of the bladder tumor is useful for bladder preservation in certain patients with invasive bladder cancer. Patients with stage T2 tumors are best suited for this type of therapy. Keywords Bladder cancer Intra-arterial Cisplatin Organ preservation Preoperative chemotherapy
Background Radical cystectomy is the current gold standard for treatment of muscle-invasive bladder cancer (MIBC), and the 5-year overall survival rate for patients with this disease has been reported to range from 45 to 68 % [1–3]. However, because radical cystectomy requires urinary diversion, which adversely affects the patient’s quality of life (QoL), many patients choose not to accept this treatment. Although the application of an orthotopic neobladder has to some extent improved the QoL for these patients, this technique does not provide an alternative equal to the native bladder. Furthermore, due to their older age or the presence of multiple comorbidities, many MIBC patients are not ideal candidates for radical cystectomy. Recently, organ conservation procedures have become the standard methods used for treating breast, anus, larynx, and prostate cancers. Bladder preservation therapy (BPT) is one such treatment option which offers survival and localized disease control rates similar to those achieved with nonpreservation methods, when used for treatment of disease
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in qualified patients who are unsuitable for radical cystectomy. The most common BPTs utilized are transurethral resection (TUR) monotherapy, radiotherapy alone, and combined modality therapy [4–12]. Each of these methods has its own advantages and disadvantages, and no uniform optimal protocol for any of these methods has been established. Patients are most likely to accept the treatment which has the lowest rate of complications, is most economical, and is most likely to produce a satisfactory prognosis and higher quality of life. Intra-arterial chemotherapy (IAC) has been used in treatment of MIBC as a means of reducing systemic toxicity and improving local control of disease [13]. Currently, reports on the use of IAC as bladder preservation therapy have mostly focused on applications in adjuvant intraarterial chemotherapy, and reports on use of IAC as neoadjuvant arterial chemotherapy are rare. At our institution, we performed cisplatin-based intra-arterial chemotherapy followed by transurethral resection of the bladder tumor (TURBT) as a BPT strategy in a group of metastasis-free muscle-invasive bladder cancer (MIBC) patients who were unwilling or unable to undergo radical cystectomy. These patients had also previously rejected radiotherapy as a treatment option. We then retrospectively analyzed the long-term survival and treatment response for these patients, and confirmed that this treatment protocol could be successfully used as a BPT in MIBC patients.
Methods and patients A total of 135 patients diagnosed as metastasis-free muscle-invasive bladder cancer (clinical stage, T2-T4aN0M0) were enrolled in this study between August 2005 and October 2012. All patients had been informed that the current standard treatment for MIBC was radical cystectomy, but had chosen to retain their bladder because they did not want to accept urinary diversion and the possible associated changes in lifestyle. This decision was also made on the basis of other patient-specific factors, such as age or comorbidities, that would exclude surgical intervention. The protocol for this study was approved by the Institutional Ethics Committee of Shanghai First People’s Hospital (Shanghai, China), and a signed inform consent was obtained from all patients prior to enrollment. Pretreatment evaluations included a routine blood examination, serum biochemistry, chest X-ray, intravenous pyelography, cystoscopy, urinary cytology, and computerized tomography (CT) or magnetic resonance imaging (MRI) of the abdominal and pelvic areas. When necessary, a positron emission tomography—computed tomography (PET/CT) scan was also conducted. Patients enrolled in this study were required to have adequate renal, marrow,
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and cardiopulmonary function, and no evidence of lymph node metastases, distant metastases, or another concomitant malignancy. Patients who had received prior pelvic irradiation or systemic chemotherapy for bladder cancer were excluded from this study. The histological type of all cases was transitional cell carcinoma. Treatment protocol The treatment protocol is shown in the Fig. 1. Following pretreatment assessment, intra-arterial chemotherapy was administered using Seldinger’s method. Drugs were injected over 30–60 min time periods via catheters inserted into the bilateral internal iliac arteries. The superior gluteal arteries were embolized prior to initiation of chemotherapy. Intra-arterial chemotherapy was administered at 4-week intervals, and each course consisted of cisplatin (50 mg/m2), epirubicin (30 mg/m2), and 5 fluorouracil (1 g/30 mg of camptothecin). Blood routine examination and serum biochemistry were performed after each course of intra-arterial chemotherapy. Cystoscopy and CT/MRI was performed to evaluate the efficacy of each previous round of intra-arterial chemotherapy. If the tumor showed a decrease in size, the patient was allowed to proceed to the next course of intra-arterial chemotherapy; if the tumor size remained static or indicated disease progression, treatment by cystectomy was strongly recommended. At 1 month after the third course of intra-arterial chemotherapy, TURBT was performed to completely remove the tumor. Within 24 h after TURBT, patients received intra-vesical therapy with 50 mg of
Fig. 1 Treatment protocol for bladder preservation
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epirubicin and weekly maintenance therapy for 8 weeks, followed by maintenance treatment 2 years at monthly intervals.
Table 1 Patient characteristics
Evaluation of response and patient follow-up
Age (year)
Factors
Median (range)
At 1–2 months after TURBT, patient response was evaluated by cystoscopy with biopsy, abdomino-pelvic CT/MRI, and urine cytology. Complete response (CR) was defined as the absence of any residual tumor in a transurethral biopsy, a negative cytology result, and the absence of lymph node or distant metastasis as determined by a CT/MRI scan. Patients exhibiting a CR were carefully monitored, and patients who did not achieve a CR were strongly advised to undergo a radical cystectomy. Alternative treatments were selected based on the patient’s age, performance status, and preferences. During the first 2 years following treatment, patients were monitored every 3 months by cystoscopy, urinary cytology, and an ultrasound of the urinary tract, and then monitored every 6 months by performing a chest X-ray and enhanced abdomino-pelvic CT or MRI. If necessary, intravenous pyelography and bone scintigraphy were also performed. Beginning at 2 years after treatment, all patients were observed at 6-month intervals, and if recurring MIBC was found, radical cystectomy was strongly recommended. Patients who showed a recurrence of non-muscle-invasive bladder cancer (NMIBC) were treated with TURBT combined with epirubicin instillation therapy. Statistical analysis Univariate and multivariate analyses of factors associated with CR were conducted using Fisher’s exact test and a logistic regression analysis, respectively. Survival data were analyzed using the Kaplan–Meier method and a logrank test. Factors associated with patient survival were analyzed using Cox regression analysis. All analyses were performed SAS V8 statistical software (SAS Institute Inc., Cary, NC, USA), and P values \0.05 were considered statistically significant.
Results Short-term treatment response and long-term survival Among the 135 patients enrolled in this study, 127 patients completed BPT, and eight patients underwent a radical cystectomy following 2 courses of intra-arterial chemotherapy because their tumors had failed to respond to intraarterial chemotherapy. The clinical characteristics of the 127 patients who completed BPT are shown in Table 1. The median follow-up period for these patients was
Total (%) n = 127
68.8 (36–100)
Gender Male Female
103 (81.1) 24 (18.9)
Number Single Multiple
59 (46.5) 68 (53.5)
T stage T2
74 (58.3)
T3–T4a
53 (41.7)
Histology G2
53 (41.7)
G3
74 (58.3)
Size \3 cm
56 (44.1)
C3 cm
71 (55.9)
\5 cm
97 (76.4)
C5 cm
30 (23.6)
Location Wall Trigone/Neck Hydronephrosis
80 (63.0) 47 (37.0)
Yes
64 (77.1)
No
19 (22.9)
For reasons of study design, hydronephrosis data were collected for only 83 patients
31.9 months (range 5–87 months). Ninety-one patients (71.7 %) showed an initial CR, and the 5-year overall survival and disease-specific survival rates for all patients were 50.2 and 59.5 %, respectively (Fig. 2a, b). Among the 36 non-CR patients, 16 underwent radical cystectomy, and among that group, six patients died of disease progression, while two patients died of other unrelated diseases. Twenty patients refused or were found unsuitable for the radical cystectomy and underwent TURBT or partial cystectomy to remove their tumor. Among these 20 patients, 10 were treated with systemic chemotherapy alone or chemotherapy combined with radiotherapy, five patients continued to receive intra-arterial chemotherapy, and five patients only received best supportive care. The median survival time for these thirty patients was 12.9 months. Disease recurrence and progression Among the 91 patients who demonstrated an initial CR, 25 experienced a recurrence of their bladder tumor. The 10
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Fig. 2 Survival curves. a Overall survival and b disease-specific survival for all patients; c recurrence-free survival and d progression-free survival for patients with CR; e overall survival and f disease-specific survival according to clinical stage (T2 vs. T3–T4a)
patients who experienced a recurrence of non-muscleinvasive cancer were treated with TURBT and instillation therapy, and two of these patients required an extra course of intra-arterial chemotherapy. Among the patients who displayed disease progression, 4 showed distant metastasis and were treated with systemic chemotherapy. Among the 11 patients who displayed a localized recurrence of MIBC, 6 underwent radical cystectomy, while the others refused cystectomy and received a second cycle of bladder preservation therapy. The 5-year recurrence-free and progression-free survival rates among the patients who demonstrated a complete response were 62.2 and 76.9 %, respectively (Fig. 2c, d). Prognostic factors for CR and overall survival Our analysis of tumor characteristics showed that clinical stage, tumor size (\3 cm), and the presence of
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hydronephrosis were all significantly correlated with CR; however, the multivariate analysis showed that clinical stage (P = 0.0384) and location (P = 0.0462) were identified as significant prognostic factors (Table 2). Due to reasons associated with study design, a complete data set for hydronephrosis was not available, and further multivariate analyses could not be conducted for its importance as a prognostic factor. Clinical stage was significantly associated with both overall survival (P = 0.0229) and disease-specific survival (P = 0.0486) (Fig. 2e, f). Additionally, analysis by univariate Cox regression showed that a tumor size \5 cm and clinical stage were both significantly correlated with increased rates of overall survival (Table 3). However, the stepwise Cox regression analysis showed that only clinical stage was significantly associated with improved overall survival (P = 0.0262, HR = 1.986, 95 % CI 1.085– 3.638).
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Toxicity Toxicities associated with treatment were evaluated according to the Common Terminology Criteria for Adverse Events, version 3.0 (CTCAE). The treatment regimens used in this study were well tolerated by all patients; however, 31 patients experienced gastrointestinal toxicity. Symptoms in these patients included nausea (20
Table 2 Factors evaluated for prediction of an initial CR Factors
Univariate
Multivariate
CR (%)
P value
\70 year
50 (78.1)
0.1182
C70 year
41 (65.1)
OR (95 % CI)
P value
patients), vomiting (18 patients), anorexia (27 patients), and diarrhea (4 patients). Complications resulting from leukocytopenia and anemia occurred only in seven patients, and no patients required treatment with granulocyte colony-stimulating factor (G-CSF) or transfusion of red blood cells. Other complication like ischialgia developed in 8 cases. Most adverse events occurred as grade 1/2. Grade 3 toxicity occurred in five patients with gastrointestinal symptoms, and grade 4 toxicity occurred in only one patients with diarrhea. The severity of all adverse effects improved following completion of treatment for bladder cancer or a specific symptomatic treatment. No patient discontinued treatment due to a clinical complication.
Age
Discussion
Gender Male
75 (72.8)
Female
16 (66.7)
0.6167
Number Single
45 (76.3)
Multiple
46 (67.6)
0.3268
1.078 (0.45–2.579)
0.8666
0.0089
2.567 (1.052–6.264)
0.0384
0.842
1.974 (0.41–2.312)
0.9519
0.0285
1.982 (0.723–5.434)
0.184
0.1119
1.055 (0.368–3.025)
0.9213
0.068
2.367 (1.015–5.521)
0.0462
T stage T2
60 (81.1)
T3–T4a
31 (58.5)
Histology G2
39 (73.6)
G3
52 (70.3)
Size \3 cm
46 (82.1)
C3 cm
45 (63.4)
\5 cm
73 (75.3)
C5 cm
18 (60)
Location Wall
62 (77.5)
Trigone/Neck
29 (61.7)
Hydronephrosis Yes
42 (65.6)
No
7 (36.8)
0.0341
CR complete response, OR odds ratio, CI confidence interval
Table 3 Univariate Cox regression analysis of survival
HR hazard ratio, CI confidence interval
Factors
Conservative methods can be used in treatment of MIBC to increase survival rates, reduce complications, retain original bladder function, and improve QoL. The CR and 5-year overall survival rates following BPT have been reported to range from 60 to 80 and from 45 to 75 %, respectively [8– 15]; however, a uniform optimal BPT protocol has yet to be established. For example, TUR, when used as monotherapy for MIBC, can only be applied to treat a tumor \3 cm in size located in the superficial muscle layer and in patients without evidence of hydronephrosis [4–6]. In contrast to use of radiotherapy alone, chemoradiotherapy has been shown to improve local control without increasing the incidence of other complications [16]. However, chemotherapy has been associated with a higher incidence of serious acute drug-related toxicities [12, 16], while radiotherapy appears to increase the risk of other serious complications, such as radiation cystitis [17]. Administration of a specific dose of an anti-cancer agent via intra-arterial infusion leads to a higher local peak plasma concentration of the drug and an increased area under the plasma concentration–time curve. This results in a higher measurable concentration of drug within the tumor, leading to improved local control and less systemic toxicity [18]. Our results confirm that use of intra-arterial
Overall survival
Disease-specific survival
P value
HR
95 % CI
P value
HR
95 % CI
T stage (T2 vs. T3–T4a)
0.0262
1.986
1.085–3.638
0.0533
1.939
0.991–3.795
Number (single vs. multiple)
0.4980
1.229
0.677–2.232
0.8164
0.925
0.481–1.781
Size 1 (\3 vs. C3 cm)
0.3948
1.306
0.706–2.417
0.4095
1.333
0.673–2.639
Size 2 (\5 vs. C5 cm)
0.0467
1.860
1.009–3.429
0.0615
1.915
0.969–3.785
Location (wall vs. others)
0.3156
1.201
0.840–1.717
0.8673
1.036
0.683–1.573
Grade (G2 vs. G3)
0.2754
1.285
0.819–2.018
0.5460
1.170
0.702–1.951
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chemotherapy for purposes of bladder preservation can produce effective local control of MIBC. In our study, the 5-year overall survival rates were similar to those achieved using radical cystectomy or other BPT protocols. Additionally, several literature reports support our finding that intra-arterial chemotherapy can be successfully used to treat muscle-invasive bladder cancer [13, 18, 19]. In the present study, we performed intra-arterial chemotherapy prior to TUR. Neo-adjuvant chemotherapy has been shown to improve 5-year survival rates of MIBC patients by at least 5 % [20, 21]. Additionally, Mori et al. [22] considered the fact that neo-adjuvant intra-arterial chemotherapy does not cause severe adhesions during radical cystectomy in non-CR patients. Meanwhile, in clinical practice, we found that preoperative intra-arterial chemotherapy provides several additional advantages. First, this method allows for evaluation of a tumor’s sensitivity to intra-arterial chemotherapy. This is an important consideration because the decision on whether to continue to the next course of intra-arterial chemotherapy or turn to use of radical cystectomy is critical for reducing unnecessary treatment and avoiding delays in therapy. Second, preoperative intra-arterial chemotherapy often results in decreases in tumor size and severity, which facilitate easy and complete removal of the lesion. These effects are also preservation of the bladder. In our study, we strictly excluded patients with distant and lymph node metastases, and our standards for a CR did not include the presence or absence of such metastases. This criterion could have artificially lessened the influence of lymph node metastases and tumor micrometastases on patient outcomes. Due to differences in tumor clinical and pathological characteristics, and also patient survival rates and prognoses, not all MIBC patients without evidence of a distant metastasis are suitable for BPT. However, some studies have reported that several factors, including tumor stage, evidence of hydronephrosis at the time of diagnosis, completion of TURBT, presence of CIS, and completeness of response to induction treatment, contribute to the prognosis for patients treated with BPT [8–10, 15, 23]. CR rates for T2 tumors have been reported to range from 71 to 88 %, and CR rates for grades T3–4 tumors range from 57 to 72 % [24]. A study conducted with 348 patients at Massachusetts General Hospital showed that both tumor stage and a CR to induction therapy were significant predictors of survival.8 Moreover, Rodel et al. [10] confirmed that tumor factors such as presentation at an early disease stage, being unifocal, and also evidence of complete TUR should be considered when determining candidacy for combined modality treatment. The statistical analyses conducted in our current study showed that tumor stage was significantly associated with both CR and overall
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survival. Furthermore, we specifically identified patients with a clinical stage T2 tumor as the best candidates to receive bladder preservation therapy using our regimen. Based on the location in the body, we subdivided tumors into 2 groups: bladder wall and bladder neck or trigone. The fundus and the base of the bladder are supplied by different branches of the vesical artery [25]. Therefore, depending on location, effective drug delivery will be dose dependent. Our results show that in multivariate analysis, the location of a tumor was significantly correlated with CR. Although this result need more clinical trials to test, and more stringent location classification criteria must be employed, we believe the tumor location should be taken into account as an additional predictive factor. Currently, there are no published results of any randomized clinical trial directly comparing radical cystectomy with BPT. Therefore, the value of the bladder preservation approach in terms of long-term cure rates remains to be established. Additionally, the criteria used for optimal selection of patients to receive this treatment require further investigation and verification. Our report describes the effectiveness of preoperative intra-arterial chemotherapy in treatment of MIBC and suggests IAC as an alternative treatment option for patients who are either unwilling or unable to accept radical surgery. However, there were some limitations to our study that should to be considered. First, our study analyzed treatment outcomes in a relatively small number of patients, and further studies with larger patient numbers, longer follow-up times, and including a greater number of clinical variables are required to further validate our results. Second, the protocol used for patient treatment in own study requires further re-design and optimization to improve CR rates. Furthermore, randomized clinical studies comparing the efficacy of neo-adjuvant intra-arterial chemotherapy with that of adjuvant chemotherapy need to be conducted.
Conclusions In conclusion, combined treatment with preoperative intraarterial chemotherapy and TURBT represents a conservative treatment option for patients with localized MIBC. We propose that the best candidates for this combination therapy are patients with stage T2 tumors. Conflict of interest
None declared.
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Page 7 of 7 912 13. Mokarim A, Uetani M, Hayashi N, Sakamoto I, Minami K, Ogawa Y, et al. Combined intraarterial chemotherapy and radiotherapy in the treatment of bladder carcinoma. Cancer. 1997;80(9):1776–85. 14. Tsukamoto S, Ishikawa S, Tsutsumi M, Nakajima K, Sugahara S. An organ-sparing treatment using combined intra-arterial chemotherapy and radiotherapy for muscle-invading bladder carcinoma. Scand J Urol Nephrol. 2002;36(5):339–43. 15. Chung PW, Bristow RG, Milosevic MF, Yi QL, Jewett MA, et al. Long-term outcome of radiation-based conservation therapy for invasive bladder cancer. Urol Oncol. 2007;25(4):303–9. 16. James ND, Hussain SA, Hall E, Jenkins P, Tremlett J, Rawlings C, et al. Radiotherapy with or without chemotherapy in muscleinvasive bladder cancer. N Engl J Med. 2012;366(16):1477–88. 17. Martı´nez-Rodrı´guez R, Areal Calama J, Buisan Rueda O, Gonza´lez Satue C, Sanchez Macias J, et al. Practical treatment approach of radiation induced cystitis. Actas Urol Esp. 2010;34(7):603–9. 18. Eapen L, Stewart D, Collins J, Peterson R. Effective bladder sparing therapy with intra-arterial cisplatin and radiotherapy for localized bladder cancer. J Urol. 2004;172(4 Pt 1):1276–80. 19. Miyanaga N, Akaza H, Okumura T, Sekido N, Kawai K, Shimazui T, et al. A bladder preservation regimen using intra-arterial chemotherapy and radiotherapy for invasive bladder cancer: a prospective study. Int J Urol. 2000;7(2):41–8. 20. Advanced Bladder Cancer (ABC) Meta-analysis Collaboration. Neoadjuvant chemotherapy in invasive bladder cancer: a systematic review and meta-analysis. Lancet. 2003;361(9373): 1927–34. 21. Advanced Bladder Cancer (ABC) Meta-analysis Collaboration. Neoadjuvant Chemotherapy in invasive bladder cancer: update of a systematic review and meta-analysis of individual patient data. Eur Urol. 2005;48(2):202–6. 22. Mori K-I, Nomata K, Noguchi M, Eguchi J, Hayashi N, Kanetake H. Long-term follow up of patients with invasive bladder carcinoma receiving combined cisplatin-based intra-arterial chemotherapy and radiotherapy. Int J Urol. 2007;14(7):591–4. 23. Hara T, Nishijima J, Miyachika Y, Yamamoto Y, Sakano S, Matsuyama H. Primary cT2 bladder cancer: a good candidate for radiotherapy combined with cisplatin for bladder preservation. Jan J Clin Oncol. 2011;41(7):902–7. 24. Rene NJ, Cury FB, Souhami L. Conservative treatment of invasive bladder cancer. Curr Oncol. 2009;16(4):36–47. 25. Standring S: Bladder, prostate and urethra. In: Gray’s Anatomy, 40th edn. New York: Churchill Livingstone Elsevier, 2008, p1249.
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ORIGINAL PAPER
Organ preservation for muscle-invasive bladder cancer by preoperative intra-arterial chemotherapy and transurethral resection Bangmin Han • Shengjie Liang • Yifeng Jing • Di Cui • Xiao An • Qingsong Zou • Haibin Wei Shujie Xia
•
Received: 14 January 2014 / Accepted: 4 March 2014 / Published online: 14 March 2014 Ó Springer Science+Business Media New York 2014
Abstract The aim of this study was to evaluate the clinical outcomes achieved by use of preoperative intraarterial chemotherapy and transurethral resection of bladder tumors as bladder preservation therapy in treatment of muscle-invasive bladder cancer. Patients with clinical stage T2-T4aN0M0 muscle-invasive bladder cancer were treated with 3 courses of preoperative cisplatin-based intra-arterial chemotherapy at 4-week intervals. Following treatment, the tumors were completely removed by transurethral resection, and all patients received epirubicin for intravesical instillation as a maintenance strategy. Patients showing a complete response received continuous monitoring, and radical cystectomy was strongly recommended for patients who did not achieve a complete response. Between August 2005 and October 2012, a total of 127 patients completed treatment with a bladder preservation therapy, and the median follow-up time for all patients was 31.9 months (range 5–87 months). Among these patients, 91 (71.7 %) achieved a complete response, and the 5-year overall survival and disease-specific survival rates for all patients were 50.2 and 59.5 %, respectively. Among the patients who demonstrated a complete response, 10 experienced a superficial relapse and 15 experienced an invasive cancer relapse. The 5-year recurrence-free and
B. Han S. Liang Y. Jing D. Cui Q. Zou H. Wei S. Xia (&) Department of Urology, Shanghai First People’s Hospital Affiliated to Shanghai Jiaotong University, No. 100, Haining Road, Shanghai 200080, China e-mail: [email protected]; [email protected] X. An Department of Vascular Surgery and Interventional Radiology, Shanghai First People’s Hospital Affiliated to Shanghai Jiaotong University, No. 100, Haining Road, Shanghai 200080, China
progression-free survival rates were 62.2 and 76.9 %, respectively. An analysis of tumor-related factors suggested that clinical stage was significant for predicting both complete response and overall survival. These results suggest that preoperative intra-arterial chemotherapy combined with transurethral resection of the bladder tumor is useful for bladder preservation in certain patients with invasive bladder cancer. Patients with stage T2 tumors are best suited for this type of therapy. Keywords Bladder cancer Intra-arterial Cisplatin Organ preservation Preoperative chemotherapy
Background Radical cystectomy is the current gold standard for treatment of muscle-invasive bladder cancer (MIBC), and the 5-year overall survival rate for patients with this disease has been reported to range from 45 to 68 % [1–3]. However, because radical cystectomy requires urinary diversion, which adversely affects the patient’s quality of life (QoL), many patients choose not to accept this treatment. Although the application of an orthotopic neobladder has to some extent improved the QoL for these patients, this technique does not provide an alternative equal to the native bladder. Furthermore, due to their older age or the presence of multiple comorbidities, many MIBC patients are not ideal candidates for radical cystectomy. Recently, organ conservation procedures have become the standard methods used for treating breast, anus, larynx, and prostate cancers. Bladder preservation therapy (BPT) is one such treatment option which offers survival and localized disease control rates similar to those achieved with nonpreservation methods, when used for treatment of disease
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in qualified patients who are unsuitable for radical cystectomy. The most common BPTs utilized are transurethral resection (TUR) monotherapy, radiotherapy alone, and combined modality therapy [4–12]. Each of these methods has its own advantages and disadvantages, and no uniform optimal protocol for any of these methods has been established. Patients are most likely to accept the treatment which has the lowest rate of complications, is most economical, and is most likely to produce a satisfactory prognosis and higher quality of life. Intra-arterial chemotherapy (IAC) has been used in treatment of MIBC as a means of reducing systemic toxicity and improving local control of disease [13]. Currently, reports on the use of IAC as bladder preservation therapy have mostly focused on applications in adjuvant intraarterial chemotherapy, and reports on use of IAC as neoadjuvant arterial chemotherapy are rare. At our institution, we performed cisplatin-based intra-arterial chemotherapy followed by transurethral resection of the bladder tumor (TURBT) as a BPT strategy in a group of metastasis-free muscle-invasive bladder cancer (MIBC) patients who were unwilling or unable to undergo radical cystectomy. These patients had also previously rejected radiotherapy as a treatment option. We then retrospectively analyzed the long-term survival and treatment response for these patients, and confirmed that this treatment protocol could be successfully used as a BPT in MIBC patients.
Methods and patients A total of 135 patients diagnosed as metastasis-free muscle-invasive bladder cancer (clinical stage, T2-T4aN0M0) were enrolled in this study between August 2005 and October 2012. All patients had been informed that the current standard treatment for MIBC was radical cystectomy, but had chosen to retain their bladder because they did not want to accept urinary diversion and the possible associated changes in lifestyle. This decision was also made on the basis of other patient-specific factors, such as age or comorbidities, that would exclude surgical intervention. The protocol for this study was approved by the Institutional Ethics Committee of Shanghai First People’s Hospital (Shanghai, China), and a signed inform consent was obtained from all patients prior to enrollment. Pretreatment evaluations included a routine blood examination, serum biochemistry, chest X-ray, intravenous pyelography, cystoscopy, urinary cytology, and computerized tomography (CT) or magnetic resonance imaging (MRI) of the abdominal and pelvic areas. When necessary, a positron emission tomography—computed tomography (PET/CT) scan was also conducted. Patients enrolled in this study were required to have adequate renal, marrow,
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and cardiopulmonary function, and no evidence of lymph node metastases, distant metastases, or another concomitant malignancy. Patients who had received prior pelvic irradiation or systemic chemotherapy for bladder cancer were excluded from this study. The histological type of all cases was transitional cell carcinoma. Treatment protocol The treatment protocol is shown in the Fig. 1. Following pretreatment assessment, intra-arterial chemotherapy was administered using Seldinger’s method. Drugs were injected over 30–60 min time periods via catheters inserted into the bilateral internal iliac arteries. The superior gluteal arteries were embolized prior to initiation of chemotherapy. Intra-arterial chemotherapy was administered at 4-week intervals, and each course consisted of cisplatin (50 mg/m2), epirubicin (30 mg/m2), and 5 fluorouracil (1 g/30 mg of camptothecin). Blood routine examination and serum biochemistry were performed after each course of intra-arterial chemotherapy. Cystoscopy and CT/MRI was performed to evaluate the efficacy of each previous round of intra-arterial chemotherapy. If the tumor showed a decrease in size, the patient was allowed to proceed to the next course of intra-arterial chemotherapy; if the tumor size remained static or indicated disease progression, treatment by cystectomy was strongly recommended. At 1 month after the third course of intra-arterial chemotherapy, TURBT was performed to completely remove the tumor. Within 24 h after TURBT, patients received intra-vesical therapy with 50 mg of
Fig. 1 Treatment protocol for bladder preservation
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epirubicin and weekly maintenance therapy for 8 weeks, followed by maintenance treatment 2 years at monthly intervals.
Table 1 Patient characteristics
Evaluation of response and patient follow-up
Age (year)
Factors
Median (range)
At 1–2 months after TURBT, patient response was evaluated by cystoscopy with biopsy, abdomino-pelvic CT/MRI, and urine cytology. Complete response (CR) was defined as the absence of any residual tumor in a transurethral biopsy, a negative cytology result, and the absence of lymph node or distant metastasis as determined by a CT/MRI scan. Patients exhibiting a CR were carefully monitored, and patients who did not achieve a CR were strongly advised to undergo a radical cystectomy. Alternative treatments were selected based on the patient’s age, performance status, and preferences. During the first 2 years following treatment, patients were monitored every 3 months by cystoscopy, urinary cytology, and an ultrasound of the urinary tract, and then monitored every 6 months by performing a chest X-ray and enhanced abdomino-pelvic CT or MRI. If necessary, intravenous pyelography and bone scintigraphy were also performed. Beginning at 2 years after treatment, all patients were observed at 6-month intervals, and if recurring MIBC was found, radical cystectomy was strongly recommended. Patients who showed a recurrence of non-muscle-invasive bladder cancer (NMIBC) were treated with TURBT combined with epirubicin instillation therapy. Statistical analysis Univariate and multivariate analyses of factors associated with CR were conducted using Fisher’s exact test and a logistic regression analysis, respectively. Survival data were analyzed using the Kaplan–Meier method and a logrank test. Factors associated with patient survival were analyzed using Cox regression analysis. All analyses were performed SAS V8 statistical software (SAS Institute Inc., Cary, NC, USA), and P values \0.05 were considered statistically significant.
Results Short-term treatment response and long-term survival Among the 135 patients enrolled in this study, 127 patients completed BPT, and eight patients underwent a radical cystectomy following 2 courses of intra-arterial chemotherapy because their tumors had failed to respond to intraarterial chemotherapy. The clinical characteristics of the 127 patients who completed BPT are shown in Table 1. The median follow-up period for these patients was
Total (%) n = 127
68.8 (36–100)
Gender Male Female
103 (81.1) 24 (18.9)
Number Single Multiple
59 (46.5) 68 (53.5)
T stage T2
74 (58.3)
T3–T4a
53 (41.7)
Histology G2
53 (41.7)
G3
74 (58.3)
Size \3 cm
56 (44.1)
C3 cm
71 (55.9)
\5 cm
97 (76.4)
C5 cm
30 (23.6)
Location Wall Trigone/Neck Hydronephrosis
80 (63.0) 47 (37.0)
Yes
64 (77.1)
No
19 (22.9)
For reasons of study design, hydronephrosis data were collected for only 83 patients
31.9 months (range 5–87 months). Ninety-one patients (71.7 %) showed an initial CR, and the 5-year overall survival and disease-specific survival rates for all patients were 50.2 and 59.5 %, respectively (Fig. 2a, b). Among the 36 non-CR patients, 16 underwent radical cystectomy, and among that group, six patients died of disease progression, while two patients died of other unrelated diseases. Twenty patients refused or were found unsuitable for the radical cystectomy and underwent TURBT or partial cystectomy to remove their tumor. Among these 20 patients, 10 were treated with systemic chemotherapy alone or chemotherapy combined with radiotherapy, five patients continued to receive intra-arterial chemotherapy, and five patients only received best supportive care. The median survival time for these thirty patients was 12.9 months. Disease recurrence and progression Among the 91 patients who demonstrated an initial CR, 25 experienced a recurrence of their bladder tumor. The 10
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Fig. 2 Survival curves. a Overall survival and b disease-specific survival for all patients; c recurrence-free survival and d progression-free survival for patients with CR; e overall survival and f disease-specific survival according to clinical stage (T2 vs. T3–T4a)
patients who experienced a recurrence of non-muscleinvasive cancer were treated with TURBT and instillation therapy, and two of these patients required an extra course of intra-arterial chemotherapy. Among the patients who displayed disease progression, 4 showed distant metastasis and were treated with systemic chemotherapy. Among the 11 patients who displayed a localized recurrence of MIBC, 6 underwent radical cystectomy, while the others refused cystectomy and received a second cycle of bladder preservation therapy. The 5-year recurrence-free and progression-free survival rates among the patients who demonstrated a complete response were 62.2 and 76.9 %, respectively (Fig. 2c, d). Prognostic factors for CR and overall survival Our analysis of tumor characteristics showed that clinical stage, tumor size (\3 cm), and the presence of
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hydronephrosis were all significantly correlated with CR; however, the multivariate analysis showed that clinical stage (P = 0.0384) and location (P = 0.0462) were identified as significant prognostic factors (Table 2). Due to reasons associated with study design, a complete data set for hydronephrosis was not available, and further multivariate analyses could not be conducted for its importance as a prognostic factor. Clinical stage was significantly associated with both overall survival (P = 0.0229) and disease-specific survival (P = 0.0486) (Fig. 2e, f). Additionally, analysis by univariate Cox regression showed that a tumor size \5 cm and clinical stage were both significantly correlated with increased rates of overall survival (Table 3). However, the stepwise Cox regression analysis showed that only clinical stage was significantly associated with improved overall survival (P = 0.0262, HR = 1.986, 95 % CI 1.085– 3.638).
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Toxicity Toxicities associated with treatment were evaluated according to the Common Terminology Criteria for Adverse Events, version 3.0 (CTCAE). The treatment regimens used in this study were well tolerated by all patients; however, 31 patients experienced gastrointestinal toxicity. Symptoms in these patients included nausea (20
Table 2 Factors evaluated for prediction of an initial CR Factors
Univariate
Multivariate
CR (%)
P value
\70 year
50 (78.1)
0.1182
C70 year
41 (65.1)
OR (95 % CI)
P value
patients), vomiting (18 patients), anorexia (27 patients), and diarrhea (4 patients). Complications resulting from leukocytopenia and anemia occurred only in seven patients, and no patients required treatment with granulocyte colony-stimulating factor (G-CSF) or transfusion of red blood cells. Other complication like ischialgia developed in 8 cases. Most adverse events occurred as grade 1/2. Grade 3 toxicity occurred in five patients with gastrointestinal symptoms, and grade 4 toxicity occurred in only one patients with diarrhea. The severity of all adverse effects improved following completion of treatment for bladder cancer or a specific symptomatic treatment. No patient discontinued treatment due to a clinical complication.
Age
Discussion
Gender Male
75 (72.8)
Female
16 (66.7)
0.6167
Number Single
45 (76.3)
Multiple
46 (67.6)
0.3268
1.078 (0.45–2.579)
0.8666
0.0089
2.567 (1.052–6.264)
0.0384
0.842
1.974 (0.41–2.312)
0.9519
0.0285
1.982 (0.723–5.434)
0.184
0.1119
1.055 (0.368–3.025)
0.9213
0.068
2.367 (1.015–5.521)
0.0462
T stage T2
60 (81.1)
T3–T4a
31 (58.5)
Histology G2
39 (73.6)
G3
52 (70.3)
Size \3 cm
46 (82.1)
C3 cm
45 (63.4)
\5 cm
73 (75.3)
C5 cm
18 (60)
Location Wall
62 (77.5)
Trigone/Neck
29 (61.7)
Hydronephrosis Yes
42 (65.6)
No
7 (36.8)
0.0341
CR complete response, OR odds ratio, CI confidence interval
Table 3 Univariate Cox regression analysis of survival
HR hazard ratio, CI confidence interval
Factors
Conservative methods can be used in treatment of MIBC to increase survival rates, reduce complications, retain original bladder function, and improve QoL. The CR and 5-year overall survival rates following BPT have been reported to range from 60 to 80 and from 45 to 75 %, respectively [8– 15]; however, a uniform optimal BPT protocol has yet to be established. For example, TUR, when used as monotherapy for MIBC, can only be applied to treat a tumor \3 cm in size located in the superficial muscle layer and in patients without evidence of hydronephrosis [4–6]. In contrast to use of radiotherapy alone, chemoradiotherapy has been shown to improve local control without increasing the incidence of other complications [16]. However, chemotherapy has been associated with a higher incidence of serious acute drug-related toxicities [12, 16], while radiotherapy appears to increase the risk of other serious complications, such as radiation cystitis [17]. Administration of a specific dose of an anti-cancer agent via intra-arterial infusion leads to a higher local peak plasma concentration of the drug and an increased area under the plasma concentration–time curve. This results in a higher measurable concentration of drug within the tumor, leading to improved local control and less systemic toxicity [18]. Our results confirm that use of intra-arterial
Overall survival
Disease-specific survival
P value
HR
95 % CI
P value
HR
95 % CI
T stage (T2 vs. T3–T4a)
0.0262
1.986
1.085–3.638
0.0533
1.939
0.991–3.795
Number (single vs. multiple)
0.4980
1.229
0.677–2.232
0.8164
0.925
0.481–1.781
Size 1 (\3 vs. C3 cm)
0.3948
1.306
0.706–2.417
0.4095
1.333
0.673–2.639
Size 2 (\5 vs. C5 cm)
0.0467
1.860
1.009–3.429
0.0615
1.915
0.969–3.785
Location (wall vs. others)
0.3156
1.201
0.840–1.717
0.8673
1.036
0.683–1.573
Grade (G2 vs. G3)
0.2754
1.285
0.819–2.018
0.5460
1.170
0.702–1.951
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chemotherapy for purposes of bladder preservation can produce effective local control of MIBC. In our study, the 5-year overall survival rates were similar to those achieved using radical cystectomy or other BPT protocols. Additionally, several literature reports support our finding that intra-arterial chemotherapy can be successfully used to treat muscle-invasive bladder cancer [13, 18, 19]. In the present study, we performed intra-arterial chemotherapy prior to TUR. Neo-adjuvant chemotherapy has been shown to improve 5-year survival rates of MIBC patients by at least 5 % [20, 21]. Additionally, Mori et al. [22] considered the fact that neo-adjuvant intra-arterial chemotherapy does not cause severe adhesions during radical cystectomy in non-CR patients. Meanwhile, in clinical practice, we found that preoperative intra-arterial chemotherapy provides several additional advantages. First, this method allows for evaluation of a tumor’s sensitivity to intra-arterial chemotherapy. This is an important consideration because the decision on whether to continue to the next course of intra-arterial chemotherapy or turn to use of radical cystectomy is critical for reducing unnecessary treatment and avoiding delays in therapy. Second, preoperative intra-arterial chemotherapy often results in decreases in tumor size and severity, which facilitate easy and complete removal of the lesion. These effects are also preservation of the bladder. In our study, we strictly excluded patients with distant and lymph node metastases, and our standards for a CR did not include the presence or absence of such metastases. This criterion could have artificially lessened the influence of lymph node metastases and tumor micrometastases on patient outcomes. Due to differences in tumor clinical and pathological characteristics, and also patient survival rates and prognoses, not all MIBC patients without evidence of a distant metastasis are suitable for BPT. However, some studies have reported that several factors, including tumor stage, evidence of hydronephrosis at the time of diagnosis, completion of TURBT, presence of CIS, and completeness of response to induction treatment, contribute to the prognosis for patients treated with BPT [8–10, 15, 23]. CR rates for T2 tumors have been reported to range from 71 to 88 %, and CR rates for grades T3–4 tumors range from 57 to 72 % [24]. A study conducted with 348 patients at Massachusetts General Hospital showed that both tumor stage and a CR to induction therapy were significant predictors of survival.8 Moreover, Rodel et al. [10] confirmed that tumor factors such as presentation at an early disease stage, being unifocal, and also evidence of complete TUR should be considered when determining candidacy for combined modality treatment. The statistical analyses conducted in our current study showed that tumor stage was significantly associated with both CR and overall
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survival. Furthermore, we specifically identified patients with a clinical stage T2 tumor as the best candidates to receive bladder preservation therapy using our regimen. Based on the location in the body, we subdivided tumors into 2 groups: bladder wall and bladder neck or trigone. The fundus and the base of the bladder are supplied by different branches of the vesical artery [25]. Therefore, depending on location, effective drug delivery will be dose dependent. Our results show that in multivariate analysis, the location of a tumor was significantly correlated with CR. Although this result need more clinical trials to test, and more stringent location classification criteria must be employed, we believe the tumor location should be taken into account as an additional predictive factor. Currently, there are no published results of any randomized clinical trial directly comparing radical cystectomy with BPT. Therefore, the value of the bladder preservation approach in terms of long-term cure rates remains to be established. Additionally, the criteria used for optimal selection of patients to receive this treatment require further investigation and verification. Our report describes the effectiveness of preoperative intra-arterial chemotherapy in treatment of MIBC and suggests IAC as an alternative treatment option for patients who are either unwilling or unable to accept radical surgery. However, there were some limitations to our study that should to be considered. First, our study analyzed treatment outcomes in a relatively small number of patients, and further studies with larger patient numbers, longer follow-up times, and including a greater number of clinical variables are required to further validate our results. Second, the protocol used for patient treatment in own study requires further re-design and optimization to improve CR rates. Furthermore, randomized clinical studies comparing the efficacy of neo-adjuvant intra-arterial chemotherapy with that of adjuvant chemotherapy need to be conducted.
Conclusions In conclusion, combined treatment with preoperative intraarterial chemotherapy and TURBT represents a conservative treatment option for patients with localized MIBC. We propose that the best candidates for this combination therapy are patients with stage T2 tumors. Conflict of interest
None declared.
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