High-grade T1 (HGT1) urothelial carcinoma is an invasive disease with high predisposition for recurrence and progression. The optimal treatment of HGT1 disease remains controversial. Clinical HGT1 disease represents a heterogeneous group of patients with variable clinical behavior. Radical cystectomy for HGT1 disease is associated with excellent survival and offers the best opportunity for cure; however, it has a potential cost of decrease in quality of life. This article summarizes features associated with increased risk of progression and provides a framework for optimal treatment strategy with a focus on the role of radical cystectomy for HGT1 disease.
Key points
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Pathologic upstaging from initial high-grade T1 to muscle-invasive disease (≥T2) from either repeat resection or cystectomy ranges from 25% to 50% depending on whether muscle was present at initial resection.
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Long-term studies show progression rates of up to 50% for high-grade T1 urothelial carcinoma of the bladder with up to 30% cancer-specific death.
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Although there has been significant effort in identifying factors associated with aggressive behavior, molecular markers are not in routine clinical use and need further validation.
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Presence of concomitant carcinoma in situ, tumor multifocality, hydronephrosis, tumor size (greater than 3 cm), stage T1b, and presence of residual T1 at repeat resection deem a patient high risk and immediate cystectomy should be strongly considered.
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The incidence of lymph node involvement in patients treated with radical cystectomy for HGT1 bladder cancer is 12% to 15%.
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Immediate radical cystectomy can provide a cancer-specific survival of greater than 80% in properly staged patients.
Introduction
High-grade T1 (HGT1) urothelial carcinoma of the bladder is a potentially lethal disease that requires meticulous attention. The HGT1 group represents about 20% of the patients who present with non-muscle invasive bladder cancer (NMIBC). These tumors have a high propensity to recur and progress to muscle invasion with associated risk of metastasis and death. Long-term studies show progression rates as high as 50% with more than 30% of patients succumbing to the disease. As opposed to noninvasive disease (Ta or carcinoma in situ [CIS]) or muscle-invasive disease (≥T2), treatment guidelines are not concrete and considerable variation exists in treatment modalities. Most studies have short-term follow-up, making it difficult to assess the true long-term efficacy of proposed treatment regimens. There are no randomized trials comparing intravesical therapy with up-front cystectomy for HGT1 bladder cancer, making valid conclusions more difficult. The few long-term studies of intravesical therapy for initial diagnosis of HGT1disease show a discouraging rate of progression and disease-specific mortality. Further confounding the issue is the often considerable heterogeneity in the HGT1 patient population, depending on the presence or absence of CIS, multifocality, tumor differentiation, tumor within a diverticulum, and, most importantly, whether there is muscle present in the resected specimen. Although there is a refined understanding of some of the molecular mechanisms and biology of high-grade bladder cancer, the currently available tools cannot adequately differentiate patients who are best suited for aggressive initial management (ie, cystectomy).
Transurethral resection (TUR) of the bladder tumor (TURBT) alone has long been recognized as inadequate treatment, with 40% to 50% of patients progressing to stage T2 or greater disease in just 3 years. The addition of intravesical bacillus Calmette-Guérin (BCG) immunotherapy following TURBT has been shown in randomized trials to significantly improve the 10-year tumor progression-free and disease-specific survival rates compared with TURBT alone. This combination now constitutes the current standard first-line therapy. Patients who fail induction BCG therapy and/or have recurrent disease shortly following treatment are at significant risk of progression to muscle-invasive disease and radical cystectomy should be seriously considered. Second-line treatments for bladder preservation are generally not very effective. Additional intravesical agents in patients who develop a recurrence following BCG therapy include BCG plus interferon, mitomycin C, gemcitabine, Doxorubicin, docetaxel, apaziquone, various combinations of these agents, and newer investigational therapies. The outcomes of trials investigating salvage intravesical therapies are generally poor and have short follow-up. Because effective second-line bladder-sparing therapy using intravesical agents is not well established, many experts consider the standard treatment in this setting to be radical cystectomy. This article reviews the clinical and pathologic features that characterize HGT1 disease, with special emphasis on the role of early radical cystectomy.
Introduction
High-grade T1 (HGT1) urothelial carcinoma of the bladder is a potentially lethal disease that requires meticulous attention. The HGT1 group represents about 20% of the patients who present with non-muscle invasive bladder cancer (NMIBC). These tumors have a high propensity to recur and progress to muscle invasion with associated risk of metastasis and death. Long-term studies show progression rates as high as 50% with more than 30% of patients succumbing to the disease. As opposed to noninvasive disease (Ta or carcinoma in situ [CIS]) or muscle-invasive disease (≥T2), treatment guidelines are not concrete and considerable variation exists in treatment modalities. Most studies have short-term follow-up, making it difficult to assess the true long-term efficacy of proposed treatment regimens. There are no randomized trials comparing intravesical therapy with up-front cystectomy for HGT1 bladder cancer, making valid conclusions more difficult. The few long-term studies of intravesical therapy for initial diagnosis of HGT1disease show a discouraging rate of progression and disease-specific mortality. Further confounding the issue is the often considerable heterogeneity in the HGT1 patient population, depending on the presence or absence of CIS, multifocality, tumor differentiation, tumor within a diverticulum, and, most importantly, whether there is muscle present in the resected specimen. Although there is a refined understanding of some of the molecular mechanisms and biology of high-grade bladder cancer, the currently available tools cannot adequately differentiate patients who are best suited for aggressive initial management (ie, cystectomy).
Transurethral resection (TUR) of the bladder tumor (TURBT) alone has long been recognized as inadequate treatment, with 40% to 50% of patients progressing to stage T2 or greater disease in just 3 years. The addition of intravesical bacillus Calmette-Guérin (BCG) immunotherapy following TURBT has been shown in randomized trials to significantly improve the 10-year tumor progression-free and disease-specific survival rates compared with TURBT alone. This combination now constitutes the current standard first-line therapy. Patients who fail induction BCG therapy and/or have recurrent disease shortly following treatment are at significant risk of progression to muscle-invasive disease and radical cystectomy should be seriously considered. Second-line treatments for bladder preservation are generally not very effective. Additional intravesical agents in patients who develop a recurrence following BCG therapy include BCG plus interferon, mitomycin C, gemcitabine, Doxorubicin, docetaxel, apaziquone, various combinations of these agents, and newer investigational therapies. The outcomes of trials investigating salvage intravesical therapies are generally poor and have short follow-up. Because effective second-line bladder-sparing therapy using intravesical agents is not well established, many experts consider the standard treatment in this setting to be radical cystectomy. This article reviews the clinical and pathologic features that characterize HGT1 disease, with special emphasis on the role of early radical cystectomy.
Pathology
Optimal management of bladder cancer relies heavily on information garnered from TUR of the tumor. Grade, stage, and depth of tumor invasion play a fundamental role in subsequent prognostication and treatment strategies. In addition, depth of tumor invasion within the lamina propria, associated CIS, lymphovascular invasion (LVI), and aberrant differentiation all have been shown to be important risk factors for progression of HGT1 disease. Interpretation of lamina propria invasion may be difficult in TUR specimens, especially when there is a high degree of cautery artifact. In a study of centralized pathologic review of 1400 patients treated in 5 European Organization for Research and Treatment of Cancer (EORTC) randomized phase III trials comparing various adjuvant treatments for NMIBC, the investigators found significant variation in grade and stage. More than half the tumors (53%) were downstaged to Ta, whereas 10% of the cases were upstaged to muscle-invasive (T2) disease. There was agreement on the diagnosis of HGT1 disease in only 50% of the cases. In addition, there is considerable understaging of the disease, particularly when there is no muscle included in the resected specimen. The goal of TUR is eradication of the tumor whenever possible with adequate sampling of the muscularis propria. Fluorescence cystoscopy (blue light) using hexaminolevulinate (HAL) has recently been shown to improve the detection and complete resection of NMIBCs. Numerous studies have now documented up to 50% understaging when muscle is absent from the TURBT specimen. Even when muscle is present in the resected specimen, adequate staging cannot be presumed since studies have shown that, even in that setting, there is still a 10% to 15% chance of upstaging to muscle-invasive disease. These patients are destined to fail with conservative therapy because intravesical agents are ineffective in this setting. The presence of muscle in a resected specimen does not automatically imply that it was derived from the tumor base. Jancke and colleagues investigated the presence of residual tumor in what they called the ‘marginal resection’ following complete TURBT for Ta/T1 disease. A marginal resection of 7 mm was removed following macroscopic resection of all visible tumors. Of the 94 patients evaluated, 24 (26%) had residual tumor in the marginal resection, which had a significant impact on recurrence. Incomplete tumor resection not only leads to early recurrence but, more importantly, is probably the source for tumor progression and dissemination. Cystectomy series for clinical T1 disease also reflect similar understaging with 30% to 40% of patients being upstaged to muscle-invasive disease. In the series from Vanderbilt University including 78 patients, 31 patients (40%) were upstaged to T2 disease. Final pathologic stage had a significant impact on survival, with 98% of patients with pathologic stage T1 being disease free during follow-up compared with 65% with stage pT2 or greater disease ( P <.01).
Substaging
The existence of muscularis mucosae within the subepithelial connective tissue has been well described and used for prognostication. However, the degree of development of this layer is variable. The depth of tumor invasion into the lamina propria has been proved to be associated with outcome. Angulo and colleagues examined a series of 170 patients with HGT1 disease and differentiated 98 of them (58%) into those with tumor invasion confined to the lamina propria (pT1a) and those with tumor infiltrating into the submucosa (pT1b). Cox regression analysis of pT1 subcategory showed the depth of subepithelial connective tissue invasion to be an independent prognostic factor ( P <.05). Five-year recurrence-free survival (RFS) was 86% for patients with stage pT1a tumors compared with 52% of those with pT1b tumors. Several other investigators have replicated similar results corroborating the feasibility of substaging of T1 tumors. Other researchers have studied this concept with further granularity. Orsola and colleagues reported on 97 patients with T1 disease substaged according to invasion superficial to (T1a), into (T1b), or beyond the muscularis mucosae (T1c). They were able to subclassify 87% of the cases and, although the recurrence rate was similar for all groups, progression rate for deep lamina propria invasion (T1b and T1c) was significantly higher than for T1a tumors (34% vs 8%, P = .016). Multivariate analysis revealed depth of invasion and CIS to be the independent prognostic factors, with a hazard ratio (HR) of 4.47 and 3.19, respectively. However, a recent study by van Rhijn and colleagues found no association between depth of invasion and progression or disease-specific survival. However, they did introduce a novel substaging system of pT1 bladder cancer differentiating tumors into T1 microinvasive (T1m) and T1 extensive (T1e) tumors. They then determined the invasion of the muscularis mucosae–vascular plexus into T1a/b/c categories according to invasion above, into, or beyond the muscularis mucosae. They found substage (T1m/T1e) to be significant for progression and disease-specific survival but not substage according to depth of invasion (T1a/b/c). More significantly they were able to classify all 134 cases into the new substaging system (T1m/T1e). Others have corroborated the significance of microinvasive versus extensive-invasive T1 to be prognostic for recurrence, progression, and survival in the largest series of initial pT1 tumors (n = 209) reported thus far. In their study, depth of invasion into the lamina propria was also not significant. Not all patients had a restaging TURBT. The finding that extensive invasion of the lamina propria is highly prognostic can help identify patients better suited for up-front cystectomy.
Other prognostic factors
Numerous other factors have been studied in an attempt to further substratify patients into low versus high risk of progression. Although there is generally limited information obtained from a TURBT specimen, various clinicopathologic features are present that can help differentiate patients into risk categories. LVI and tumor location have been correlated with outcomes in cystectomy performed for clinical or pathologic T1 disease. In one study, nontrigonal tumor location was one of the factors significantly associated with prolonged RFS. In addition, the specimen can be submitted for molecular marker analysis, which may elucidate the underlying biologic behavior of the tumors. van Rhijn and colleagues performed a head-to-head comparison of the EORTC risk scores with 4 molecular markers in HGT1 bladder cancers treated conservatively with BCG. Their subclassification into the new system of T1m (microinvasive) versus T1e (extensive-invasive) was found to be the most important clinical variable in predicting progression to muscle-invasive disease. The study included 129 patients from two universities, and T1 substaging was performed using the new system (T1m/T1e), as well as according to depth of invasion within the lamina propria (T1a/b/c). The molecular markers studied were fibroblast growth factor receptor 3 (FGFR3) gene mutation and Ki-67, P53, P27 expression, all of which have significant prognostic value in predicting bladder cancer outcomes. Factors significant for progression were female gender, substage (T1m/T1e), and presence of CIS. Molecular markers were significant for progression in a multivariable model; however, its value was only modest. Acikalin and colleagues studied the clinical significance of maspin and Ki-67 expression in TURBT specimens from 68 patients with newly diagnosed T1 bladder cancer. Maspin expression was an independent predictor of recurrence and progression, with negative maspin expression having a 4.3 times higher risk of progression compared with maspin-positive patients. However, Ki-67 expression had no correlation with recurrence, progression, or cancer-specific mortality. Other studies of molecular markers including p53, Ki-67, Cox-2, and NMP-22 and cell cycle analysis (S phase fraction) have identified an association with increased progression risk. Although considerable effort has gone into identifying factors associated with aggressive behavior, these markers are not in routine clinical use and need validation in large series to establish whether they offer any additional information compared with routine histopathologic evaluation.
Restaging TURBT
As previously mentioned, there is significant understaging in patients with HGT1 disease. If muscle is absent from the initial resection, repeat resection to include muscularis propria at the base of the tumor resection is mandatory because there is more than 50% probability of finding muscle-invasive disease. Over the past decade or so, it has become clear that, in all patients with HGT1 disease, reresection of the tumor base is important not only from a prognostic standpoint but also as a potential therapeutic strategy. Even when muscle is present in the specimen, repeat resection can uncover occult muscle-invasive disease in at least 10% of cases, which has a profound impact on decision making.
The advantages of the restaging have been well documented and include not only better stage and risk stratification but also eradication of residual noninvasive disease for improved therapeutic response to intravesical therapy. When patients have undergone restaging TURBT, the risk of upstaging following cystectomy theoretically should be very low. This was shown in at least 1 small study from Memorial Sloan Kettering on a cohort of 71 patients with HGT1 disease of whom 15 underwent immediate cystectomy. Although 12 patients had residual disease found at cystectomy, only 2 were upstaged to muscle-invasive disease. Herr and colleagues, from the same institution, also showed that the presence of residual T1 disease on repeat TUR is associated with a significantly increased risk of progression to muscle-invasive disease. Of the 92 patients with T1 disease at reresection, 82% progressed to muscle-invasive disease at 5 years as opposed to 19% of patients with less than T1 disease (pT0, pTa, CIS). This finding is strong evidence in favor of immediate cystectomy for patients who have residual HGT1 disease on restaging TURBT. Patients should be counseled accordingly when considering conservative management. Young patients and those with life expectancy of more than 10 to 15 years should almost certainly be advised against having intravesical treatment because the risk of recurrence and progression remains well beyond 5 years. This risk is continuous in patients treated conservatively, in contrast with patients who have a cystectomy, for which relapse is rare beyond 3 years.
In addition to providing critical assessment of pathologic features of the tumor, restaging TUR also seems to improve the response to BCG therapy. Herr and colleagues compared 132 patients who underwent a single TUR before BCG therapy with 215 patients who had undergone restaging TUR. Notwithstanding the limitations of a nonrandomized comparison, 75 (57%) of the single TUR group had recurrent tumor at the first cystoscopy versus 62 (29%) of the restaging TUR group. More importantly, 45 (34%) in the former group later progressed to higher stage disease, compared with 16 (7%), respectively ( P = .001). One of the most convincing studies supporting restaging TURBT came from a randomized trial reported by Divrik and colleagues in 2010. In this trial, 210 newly diagnosed patients with HGT1 disease were randomized between a single TUR versus a restaging TUR 2 to 6 weeks following initial resection. With an adequate median follow-up of more than 5 years, recurrence (71% vs 40%), progression (24% vs 7%), and cystectomy rates (24% vs 13%) were significantly higher in the single TUR group. There were 11 deaths caused by bladder cancer in the single TUR group compared with only 5 in the second TUR group ( P = .04). This study was criticized for methodological flaws (8% of patients who were upstaged by second TUR were excluded from the study after randomization, albeit accounted for in the cystectomy rates), with probable overestimation of the benefits of second TUR. Nevertheless, there are ample data in this study to show the decreased recurrence and progression rates with a second TUR.
Treatment options
Intravesical Therapy
Over the past 2 decades, a multitude of published studies established the effectiveness of adjuvant intravesical therapy for treatment of NMIBC. Both mitomycin C and doxorubicin were shown to reduce the risk recurrence and rate of progression, with mitomycin C possibly being more effective. Over the years, BCG was shown to be superior to intravesical chemotherapy and became the treatment of choice for conservative management of high-grade disease. There are several studies reporting a wide range of recurrence and progression rates most likely because of the significant heterogeneity in the studied population including additional risk factors, use of second TUR, and use of maintenance therapy. In one of the early studies published more than 20 years ago on adjuvant BCG following TUR for HGT1 disease, Cookson and Sarosdy reported 91% tumor-free rate with a median follow-up of nearly 5 years with a progression rate of only 7%. Several randomized trials clearly documented the improvement in long-term tumor progression-free and disease-specific survival rates compared with TURBT alone. However, it became clear early on that patients who fail to achieve a complete response after the initial course of BCG were at significant risk of progression and death. Short-term follow-up does not adequately document the continuous risk of recurrence and progression compared with cystectomy series in which most recurrences occur within 3 years.
Cookson and colleagues reported the results of 15 years of follow-up of high-risk patients (CIS, T1) randomized to TUR alone or combined with intravesical BCG. Of the 86 patients enrolled, 44% had stage T1 tumors. Forty-six (53%) patients had progression and 31 (36%) eventually underwent cystectomy. The 10-year and 15-year disease-specific survival rates were 70% and 63%, respectively. At 15 years, 34% of patients overall were dead of bladder cancer, underscoring the high-risk nature of this group of patients. These results support the use of initial aggressive local therapy in patients with high-risk superficial bladder cancer. Numerous studies have published long-term results of using adjuvant BCG for HGT1 disease ( Table 1 ). Only a few studies have reported results beyond 5 years.
| Study | No. Patients | Median Follow-up (mo) | Recurrence (%) | Progression (%) | DOD (%) |
|---|---|---|---|---|---|
| Pansadoro et al, 1995 | 50 | 42 | 16 | 12 | 2 |
| Baniel et al, 1998 | 78 | 56 | 28 | 8 | 0 |
| Lebret et al, 1998 | 35 | 45 | 23 | 17 | 6 |
| Hurle et al, 1999 | 51 | 85 | 37 | 18 | 14 |
| Patard et al, 2001 | 50 | 65 | 52 | 22 | 14 |
| Kulkarni and Gupta, 2002 | 69 | 45 | 46 | 12 | 6 |
| Pansadoro et al, 2002 | 81 | 76 | 33 | 15 | 6 |
| Peyromaure et al, 2003 | 57 | 56 | 42 | 23 | 12 |
| Shahin et al, 2003 | 92 | 64 | 70 | 33 | 23 |
| Margel et al, 2007 | 78 | 107 | 35 | 18 | 16 |
Although adjuvant intravesical BCG therapy after TUR for HGT1 bladder cancer is evidently effective, the study by Shahin and colleagues showed that it may only delay the time to recurrence and cystectomy, and that BCG does not affect cancer-specific survival (CSS) in the long term. However, this study did not include maintenance therapy. In addition, a meta-analysis validated the benefit of adjuvant BCG on progression. This study, involving 24 trials and 4863 patients (including patients with Ta disease and CIS), showed a relative risk reduction of 27% for progression in patients receiving adjuvant BCG. However, this benefit was only seen in patients who received maintenance BCG therapy and overall there was no difference in treatment effect for CSS.
Predictors of Progression
Some experts advocate an initial conservative approach to HGT1 disease, with deferred cystectomy on progression. The problem with this approach is that patients allowed to progress are inherently at a disadvantage, as shown by the death rates, despite cystectomy, which range from 16% to 34%. This uncertainty has led some to investigate predictors of progression. In a review including more than 1000 patients with HGT1 disease treated with adjuvant BCG, Herr and colleagues reported progression rates ranging from 13% to 48% with a median follow-up of 5 years. This wide range suggests the concept of risk stratification in patients with HGT1 disease.
Alkhateeb and colleagues examined the prognostic significance of prior tumor resection in cases of HGT1 bladder cancer by comparing 95 primary with 96 nonprimary T1 tumors with similar clinicopathologic characteristics treated with BCG. The progression rate for the primary versus the nonprimary group was 24.2% versus 39.6%, respectively ([HR 2.07], P = .03). This difference remained significant on multivariate Cox regression analysis; however, there was no difference between the groups in regards to recurrence or disease-specific mortality. Kakiashvili and colleagues examined clinicopathologic features of 136 patients from two university centers to find predictors of recurrence and progression, and found CIS as the only independent predictor for recurrence in multivariate analysis ( P = .011). The investigators found no independent predictors of progression in 30% of the patients, many of which occurred beyond 3 years, again highlighting the significant and unpredictable risk in this patient population. Orsola and colleagues recently reported on risk factors for finding disease following BCG therapy in HGT1 disease. Tumor size and CIS were associated with finding positive disease at 3 months following initial TURBT and adjuvant BCG therapy. Other studies have corroborated the finding that the presence of CIS is associated with an increased risk of progression and death caused by disease. The EORTC has recognized associated CIS as the most significant factor associated with risk of recurrence and progression at 5 years after BCG therapy. It is therefore imperative that pathologists report associated CIS as a separate finding in the presence of HGT1 disease so patients can be counseled appropriately regarding their risk profile.
In addition, patients who have tumor recurrence and are treated with a second course of BCG are at significant risk of progression and death. In a study of 214 patients with high-risk disease who recurred with a T1 tumor, there was a 71% cumulative incidence of progression to muscle-invasive disease in those treated with a second course of BCG, with nearly half of these patients dying of disease compared with 28% of those who underwent cystectomy (31% dead of disease). Thus a HGT1 recurrence following adjuvant BCG therapy portends a poor prognosis and there is ample evidence that supports early cystectomy for this extremely high-risk patient population. Response rates to repeat BCG therapy for HGT1 disease is poor and delaying definitive therapy has a profound effect on the ultimate outcome.
Some others studies have documented a higher risk of progression with tumor morphology with solid tumors having more than twice the risk of progression and death from bladder cancer as papillary tumors. Other factors such as tumor size and aberrant histology, in addition to the number of T1 lesions (multifocality), have been associated with higher progression rates. LVI is an important pathologic finding in cystectomy specimens and has also been shown to have prognostic significance in HGT1 lesions.
Chemoradiation
The data relating to radiation therapy (RT) in the treatment of HGT1 bladder cancer are limited. There are some data suggesting that concurrent chemotherapy with RT can be effective in high-grade urothelial carcinoma. Results from Erlangen, Germany, on 84 patients with HGT1 tumors using a trimodality bladder-sparing approach with concurrent chemotherapy and radiation showed a 10-year progression-free rate of 71% and a 10-year disease-specific survival rate of 71%. More than 80% of the survivors had an intact bladder and 70% were ‘delighted’ or ‘pleased’ with their urinary function. In contrast with these promising results, a randomized trial comparing RT with conservative therapy (observation or intravesical therapy with mitomycin C [MMC] or BCG) for HGT1 disease showed no difference in progression-free survival or RFS (29% in the control vs 31% in the RT arm ( P = .65). There are few reports of the effectiveness of trimodality therapy as a second-line treatment of bladder preservation in patients with recurrent HGT1 disease following BCG therapy. The Radiation Therapy Oncology Group (RTOG) opened a clinical trial (RTOG 0926, Douglas Dahl, principal investigator) to explore the efficacy of chemoradiation in patients with HGT1 disease. To be eligible for this trial, all patients must undergo a restaging TURBT with muscularis propria present in the specimen and no evidence of muscle-invasive disease. The primary objective is avoiding cystectomy without compromising survival.
Radical cystectomy
Most cystectomy series for HGT1 tumors include patients with high-risk disease who have failed prior intravesical therapy. Because cystectomy generally represents the most aggressive and ultimate treatment of HGT1 disease, any comparison with more conservative treatment is hampered at the start by significant selection bias. Because of the substantial understaging of disease, it is important to scrutinize these series to distinguish those reporting on clinical versus pathologic T1 disease. Given the significant clinical understaging of HGT1 disease, series without restaging TURBT cannot be directly compared with those who were adequately staged. Nevertheless, the outcome from early cystectomy for HGT1 disease is generally excellent, with recurrence and disease-specific survival curves generally flattening after 2 to 3 years. In addition, the number of patients with clinical (c) T1 disease who harbor occult lymph node metastasis is important in series that include an extended pelvic lymph node dissection. In one study of 66 patients with cT1 disease, 27% of the cases were upstaged and 12% of those patients who had concomitant CIS had pathologic nodal involvement. Patients with cT1 tumors with CIS had a significantly worse CSS. Cancer-specific mortality for the cohort of patients with cT1 disease was 22% but those who had pathologic T1 disease had 10-year CSS of 92%. If cystectomy is performed when the tumor is still confined to the lamina propria, most patients are cured. If treatment is delayed until muscle invasion is clinically evident, cure rates decrease significantly.
Early Versus Delayed Cystectomy
Timing of cystectomy is of paramount importance and affects pathologic stage and outcome. There is continued debate on whether patients presenting with high-risk features can be first treated with intravesical therapy or should undergo immediate cystectomy. Notwithstanding the limitations of nonrandomized comparisons, numerous studies have shown an unfavorable effect on outcome for patients who undergo delayed cystectomy. Herr and Sogani examined the long-term outcome of 307 patients with high-risk NMIBC initially treated with TURBT and BCG, of whom 29% ultimately underwent cystectomy during a 15-year to 20-year follow-up period. Of the 90 patients who underwent cystectomy, 49% survived. Only 18% of the patients survived when cystectomy was performed for muscle-invasive disease after 2 years of follow-up, compared with 41% when cystectomy was performed before 2 years. Multivariate analysis revealed improved survival in those who underwent earlier rather than delayed cystectomy for relapse.
Although there are no randomized trials comparing early cystectomy with conservative management with intravesical therapy, Denzinger and colleagues compared the long-term outcome in patients with HGT1 disease treated with early versus deferred cystectomy for recurrent or progressive disease after initial conservative management. They compared patients who had at least 2 of the known risk factors for progression (multifocality, tumor size, and CIS) during initial TURBT. All the patients were offered up-front cystectomy and 51% opted for early cystectomy, with the other 49% undergoing deferred cystectomy for recurrence of progressive disease. Similar to all other studies, there was a 30% upstaging seen in the cystectomy specimen. The 10-year CSS was 78% in the early cystectomy cohort compared with 51% in the deferred cystectomy group ( P <.01). The presence of CIS was correlated with a lower CSS in the deferred cystectomy group. The study had selection bias because the patients who underwent deferred cystectomy had failed conservative management and therefore presumably were at higher risk than those who underwent immediate cystectomy. Nevertheless, the patients in the 2 groups were well matched and had similar initial risk factors. Because there will probably never be a randomized trial comparing immediate cystectomy with intravesical therapy, this study provides more convincing evidence that patients with HGT1 disease who have more aggressive treatment early in the course of the disease have improved outcomes.
Other investigators have published similar results. Hautmann and colleagues reported on a series of 274 patients with cT1 disease, of whom 175 were treated with immediate cystectomy compared with 99 who underwent delayed cystectomy for recurrence following intravesical treatment. The patients who underwent immediate cystectomy did not have a restaging TUR. The reported CSS was 78% for the immediate cystectomy group compared with 65% in the deferred group. The survival disadvantage in the deferred group was calculated at 17%. However, in a large series of 523 patients from Memorial Sloan Kettering with HGT1 disease who had undergone restaging TUR, Dalbagni and colleagues did not find any difference in survival between the immediate versus deferred cystectomy group. Of the 523 patients, 417 were deemed true HGT1, of whom 84 underwent immediate cystectomy. Of the 333 patients who were initially managed conservatively, 59 eventually undergoing cystectomy. The need for deferred cystectomy was higher in those who were found to have T1 disease on restaging TUR, again highlighting the high-risk nature of this group of patients and stratifying patients who would benefit most from early radical cystectomy. This series differs from the other series in that treatment approach was highly tailored and all patients underwent restaging TUR.
Results from Radical Cystectomy for HGT1 Disease
When counseling patients regarding treatment options, it is important to discuss long-term results from cystectomy performed for HGT1 disease. There are several series from high-volume centers reporting excellent outcomes for up-front radical cystectomy, for clinical T1 ( Table 2 ), or pathologic T1 disease ( Table 3 ). Gupta and colleagues reported outcomes on 167 patients with HGT1 disease who underwent radical cystectomy at 3 academic centers in the United States. Median follow-up was short at just less than 3 years. Nevertheless, the CSS was 81.5%. However, 17.5% of patients had lymph node metastases, although there was 50% understaging with 27.5% having extravesical disease. The only factor predicting disease recurrence (HR = 2.13) and mortality (HR = 2.75) was concomitant presence of CIS before cystectomy. In a larger multicenter study of 1136 patients who underwent radical cystectomy for clinical HGT1 disease, half were upstaged to muscle-invasive disease, one-third had non–organ-confined disease, and 16% had positive lymph nodes. With a median follow-up of 48 months, 36% died of metastatic bladder cancer. The investigators concluded that patients with high risk of progression may benefit from early cystectomy. However, substantial understaging and high incidence of extravesical disease argues for better clinical staging (through updated imaging, restaging TUR) to identify patients who would be candidates for neoadjuvant chemotherapy to improve survival rates.
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