Correspondence *Cleveland Clinic Taussig Cancer Center, 9500 Euclid Avenue, R35, Cleveland, OH 44195, USA

Email raghavd@ccf.org

Introduction

Although radiation has been the mainstay of nonsurgical treatment of muscle-invasive transitional cell carcinoma of the bladder for more than 50 years, cure rates have been disappointing, with 5-year survival in the range of only 30–50% (Table 1). Factors contributing to the disappointing survival rates include the reduced certainty of defining the true extent of the tumor (because of noninvasive staging techniques), the selection of patients with a poorer prognosis (patients treated with radiation tend to be older and/or with other medical comorbidities) and the fact that most high grade, invasive bladder cancers have already seeded occult metastases by the time of initial presentation.¹ The use of radiotherapy for this indication has, therefore, declined. In the US, radical cystectomy with bilateral pelvic lymph-node dissection is considered to be the gold standard for treating muscle-invasive bladder cancer,² despite the fact that, to date, no definitive randomized phase III trial has compared a modern protocol of cystectomy with radical radiotherapy (perhaps with salvage cystectomy).

Table 1 External-beam radiation therapy alone for muscle-invasive bladder cancer.

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The combined-modality treatment concept was introduced to enhance local tumor control. Initially, this involved radiotherapy (to achieve tumor downstaging) followed by cystectomy or the use of deep transurethral resection of invasive bladder cancer, followed by radiotherapy. Neither of these approaches seems to improve survival in a meaningful way. The apparent antitumor activity of systemic chemotherapy in the metastatic setting³ has led to the exploration of this modality in muscle-invasive disease in combination with standard locoregional definitive treatment. Several strategies that combine systemic chemotherapy and radiation therapy have been explored in the management of muscle-invasive bladder cancer, and these strategies have yielded better local control results than single modality therapy. This Review will provide a brief overview of radiation therapy for muscle-invasive bladder cancer but will focus on the current role of systemic chemotherapy as an integral component of the composite management plan.

Radiotherapy alone in muscle-invasive bladder cancer

A substantial body of evidence indicates that bladder cancer is a relatively radiosensitive disease. This conclusion is derived from several sources, including laboratory studies that demonstrated the high sensitivity of bladder-cancer cell lines to radiation.⁴ Table 1 summarizes the published experience with external-beam radiation therapy (EBRT) given alone as treatment for bladder cancer in series of more than 100 patients. Most of these studies are retrospective in nature, derived from single centers and reflect techniques that vary from one institution to another. There is little uniformity in imaging, field size, fluid intake restriction, dose, and fractionation, and it is clear that many questions regarding definitive radiotherapy for bladder cancer remain unresolved in the current and past literature. In fact, it is quite possible that many of the reported studies may have employed suboptimum therapeutic doses. In addition, these studies often do not delineate the changes over time in stage, radiation techniques and patient evaluation. Nevertheless, cure with the retention of acceptable bladder function can be achieved in some situations. Radical EBRT can produce a complete response in more than 50% of patients; however, only 30–50% of these patients maintain complete tumor regression without further recurrence.^{5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20} More importantly, distant metastases develop in more than 50% of patients who experienced a complete response and only one-third of patients with an initial complete response survive more than 5 years.^{5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20} Patients with higher tumor stage have a worse survival. For example, patients with T4 disease have a 2–12% long-term survival rate^{8, 12} compared with 25–59% in patients with T2 disease.^{11, 19}

Although salvage cystectomy could be considered for progressive or recurrent disease, the published experience suggests that less than 20% of patients actually undergo cystectomy. Many patients treated with radiotherapy were not initially good candidates for surgery because of locally advanced disease with bulky tumors and/or considerable medical illnesses. For the same reasons, these patients are not often considered for salvage cystectomy after initial radiation failure. Up to 80% of patients who survive over the long term after definitive EBRT-based treatment have well-functioning bladders,²¹ and patients might, thus, be very reluctant to suffer the loss of this function.

Although beyond the scope of this article, an important consideration with respect to salvage cystectomy is the dose of radiation used. In general, radiation doses in the range of 50–70 Gy, given in daily fractions of 1.8 to 2.5 Gy over 4–7 weeks, were used to treat the entire bladder, perivesical tissues, and draining lymph nodes. Dose schedules in the higher range generally achieve higher levels of local control,^{14, 16} and this pattern of dose response has been dominant in radiotherapy for the past 10–15 years. The quality of the treatment planning is critical, requiring close collaboration between the urologist and the radiation oncologist,²² and has a major impact on extent of toxicity and potential suitability for salvage cystectomy.

While no definitive phase III trial has compared cystectomy with radiotherapy, two population-based studies from Canada have suggested that radical radiotherapy with cystectomy for salvage therapy has a survival rate comparable with initial cystectomy, and has the advantage of preserving normal bladder function.^{23, 24} The veracity of this observation is clearly a function of careful case selection and of the actual case mix of the patients undergoing each modality. When one compares the sum total of published experience of radical cystectomy versus radical radiotherapy, however, it is probably fair to acknowledge higher disease-free long-term survival among the surgical patients, but these data suffer from a number of important confounding factors: heavy case-selection bias, the difficulties of comparing surgical staging and clinical staging, and different levels of intercurrent medical disease.

Preoperative radiation therapy

The initial concept of combined-modality therapy involved the use of presurgery radiotherapy with the intention of securing greater local tumor control. Whitmore reported that presurgical radiotherapy could achieve tumor downstaging, and such stage reduction was associated with improved outcome when the bladder was resected.²⁵ It was believed that this approach would reduce the likelihood of intraoperative tumor dissemination and assure a greater level of local control if the surgical procedure itself missed a portion of the tumor.²⁶ Randomized trials of planned radiotherapy before cystectomy generally preceded the use of combined chemotherapy and radiation in this disease. The largest experience with preoperative radiotherapy for bladder cancer was reported at the MD Anderson Cancer Center.²⁷ Among 338 patients with T2 to T4 disease, pathological downstaging occurred as a result of radiotherapy in 65% of cases, and 42% had no tumor in the surgical specimen. Overall survival at 5 years was 44%. Pelvic and distant recurrence rates were 16% and 43%, respectively. Preoperative radiotherapy seemed to improve pelvic control in patients with T3b disease at presentation.

The results of three studies in which patients were randomly assigned to receive planned preoperative radiotherapy and cystectomy or radical radiotherapy followed with salvage cystectomy upon recurrence are summarized in Table 2.^{28, 29, 30} The smallest and earliest study28 showed a survival difference in favor of preoperative radiation and cystectomy (46% versus 16%; P <0.01), but no survival differences were observed in the other two studies. A recent meta-analysis that combined the results of these studies also indicated improved survival with immediate cystectomy.³¹ Unfortunately, this meta-analysis has been used incorrectly by many opponents of bladder preservation to show that radical radiotherapy is inferior to cystectomy. Overall, the results are difficult to interpret because of the methodological problems, the evolution of surgical and radiotherapy techniques over the past decade, the limited use of preoperative radiotherapy in modern practice, and the availability of effective systemic chemotherapy agents. The results indicate that cystectomy and radical radiation can both be effective treatments for patients with bladder cancer when stringent criteria are used to determine the best approach on a case by case basis.

Table 2 Randomized studies of planned radiation followed by cystectomy versus definitive radiation followed by salvage cystectomy.

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Rationale for combining chemotherapy and radiotherapy

After the introduction of active chemotherapy agents for the management of metastatic bladder cancer, it seemed logical to test this approach in the 'less advanced' disease setting in combination with local definitive treatment, such as radiation therapy. This hypothesis was based on several assumptions. First, clinical and autopsy data show that micrometastases are often present at the time of presentation of invasive bladder cancer. One study examined autopsies from 367 individuals with invasive bladder cancer and identified distant metastases in 68%.³² The frequency of metastases increased with local tumor extent (pT2, 36%; pT3a, 45%; pT3b, 69%; pT4, 79%). It is, therefore, logical that chemotherapy coupled with radiation may add efficacy in reducing the rate of distant failures by eradicating occult cancer cells. Second, the optimum time to treat micrometastases is probably when their volume is minimal,³³ favoring the application of chemotherapy around the period of radiotherapy. Indeed, very small solid tumors in the laboratory contain a higher percentage of actively dividing cells than do their large counterparts.³⁴ Third, drug resistance to cytotoxic agents might be related to spontaneous mutations in cancer cells, which occurs more often in tumors of greater mass;³⁵ thus, early use of chemotherapy could overcome this problem. Fourth, hypoxic cells exist in solid tumors in regions of poor vascularity and are likely to be resistant to treatment. These cells, however, may be more sensitive to the combined effects of cytotoxic agents and radiotherapy.³⁶ Fifth, radiotherapy can induce vascular sclerosis, which causes reduced access of chemotherapy agents to tumor sites.³⁷ The administration of chemotherapy before postradiation sclerosis could thus increase responsiveness. Finally, certain chemotherapy drugs, such as 5-fluorouracil, cisplatin, gemcitabine and paclitaxel have been reported to act as 'radiosensitizers', which render normal and malignant tissues more sensitive to radiation.³⁸

Several strategies that combine systemic chemotherapy with radiation (as definitive locoregional treatment) have been explored: concurrent chemoradiation, in which chemotherapy and radiation are delivered synchronously in order to maximize radiosensitisation; neoadjuvant (pre-emptive) chemotherapy, in which chemotherapy is administered first, usually followed by assessment of response and implementation of definitive therapy; classic adjuvant therapy, in which systemic treatment is administered after completion of locoregional therapy in an attempt to control micrometastatic disease; and the combination of concurrent chemoradiation with either neoadjuvant or adjuvant chemotherapy.

Although many randomized and nonrandomized trials have been completed, the optimum timing of chemotherapy as an addition to radiation has not been defined. In this Review, we will aim to provide some of the relevant data regarding this subject, focusing mainly on the experience with neoadjuvant chemotherapy and concurrent chemoradiotherapy.

Chemotherapy and radiation in muscle-invasive bladder cancer

Radiotherapy has been combined with chemotherapy to treat bladder cancer with the goal of enhancing local control, reducing distant metastasis and possibly improving patient survival, the ultimate end point in most cancer trials. Preclinical data have shown that the most commonly used (and probably most active) single chemotherapy agent, cisplatin, can enhance the cytotoxic effects of radiation even in hypoxic cells.³⁹ Given that cisplatin can be found in tissues and urine several days after administration, some of the neoadjuvant chemotherapy schedules may in fact represent the equivalent of concomitant chemoradiation.⁴⁰

Chemoradiation

Concurrent delivery of chemotherapy and radiotherapy has been one of the strategies used to enable bladder preservation for more than 30 years.^{21, 41, 42, 43, 44, 45, 46, 47, 48, 49} Although randomized clinical trials have not demonstrated superiority of concurrent chemoradiation over radiotherapy alone, historical comparison, with all its limitations, has suggested higher response rates and improved long-term survival.^{41, 49}

Rödel et al.²¹ recently updated their large retrospective experience in over 400 patients with T1 to T4 bladder cancer (79% with T2–T4 tumors). All patients were treated with transurethral resection of the bladder tumor (TURBT) followed by pelvic radiation (54 Gy) and 289 patients (70% of the whole cohort) were treated with concurrent radiochemotherapy (cisplatin or carboplatin with or without 5-fluorouracil applied during the first and fifth week of radiation). After a median of 5 years of follow-up, clinical complete response (CR) was achieved in 72% of patients. Local control after CR without muscle-invasive relapse was maintained in 64% of patients at 10 years.²¹ Distant metastases were diagnosed in 98 patients with an actuarial rate of 35% at 10 years. Disease-specific survival at 10 years was 42%, and more than 80% of survivors showed bladder preservation. On multivariate analysis, chemoradiation was more effective than radiation alone in terms of CR (61% with radiation alone compared with 66–87% for chemoradiation, depending on the chemotherapy regimen used; P = 0.05). Multivariate analysis also showed the superiority of chemoradiation over radiation alone with respect to 10-year survival (30–52% versus 19%; P = 0.06). In addition, salvage cystectomy for local failure was associated with a 45% disease-specific survival rate at 10 years. It should be noted that although the experience of Rödel's group has been collected over a 20-year period, and before the current era of precision in radiation, investigators from Massachussets General Hospital have been reporting comparable results for the past 15 years,⁴¹ and their data have formed the basis of the current era of Radiation Therapy Oncology Group (RTOG) clinical trials in invasive bladder cancer. In both series heavy case-selection bias has been a confounding variable and the trials used different selection criteria to determine which patients should receive radiotherapy alone versus chemoradiation.

The results obtained in several larger phase I–II studies of chemoradiation are reviewed in Table 3.^{42, 43, 44, 45, 46, 47, 48, 49} Overall, CR was in the range of 70%; however, 'long-term' survival ranged from 35% to 79% at 2–5 years. Most of the trials were based on the initial bladder-tumor response to the induction therapy, with the addition of radiation or chemoradiation in cases of CR after the initial induction phase.

Table 3 Selected trials of chemoradiation for invasive bladder cancer.

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The only randomized phase III trial of radiotherapy versus concurrent chemotherapy and radiation was conducted by the National Cancer Institute of Canada.⁴⁴ Patients with T2 to T4b bladder cancer received local regional therapy alone (full-dose radiotherapy or preoperative radiotherapy and cystectomy) with or without concurrent single-agent cisplatin. At a median of 6.5 years of follow up, no difference was noted in overall survival; however, the study was not powered to reveal a survival benefit. Patients given concurrent chemotherapy had a significantly lower rate of pelvic recurrence compared with those who were treated with radiation alone (P = 0.038). No difference in the risk for serious adverse effects was reported.⁴⁴ This study had relatively small subject numbers and included two distinct treatment options. In one group the patients were treated with a bladder sparing approach and in the other they received preoperative therapy and cystectomy, with the type of definitive treatment being decided upon by both the treating specialist and patient.

Although the overall survival figures from the chemoradiation trials are somewhat comparable to recent cystectomy series at first glance,⁵⁰ the comparison with North American studies, where reported data are restricted to pathologic staging, is rather complex. A crucial element of the success of these programs has been the importance of recognizing treatment failure in high-risk patients at the earliest opportunity, which allows prompt patient referral to cystectomy. In these programs, cystoscopy is performed 4–8 weeks after the completion of chemoradiation, and radical cystectomy is advised in patients with residual cancer.

Neoadjuvant chemotherapy

The earliest clinical trials of initial chemotherapy before definitive radiotherapy were initiated in the early 1980s, and all employed single-agent chemotherapy^{51, 52, 53} using agents such as cisplatin, methotrexate or 5-fluorouracil. At the time these studies were designed, cisplatin was thought to be the most active cytotoxic agent against bladder cancer, and the role of combination chemotherapy had not yet been proven. Although the first trials employed chemotherapy before radiotherapy, the majority of randomized clinical studies have focused on testing the utility of chemotherapy followed by radical cystectomy, and these trials have mostly involved combination chemotherapy regimens. Early phase II trials with chemotherapy showed promising activity, with tumor downstaging, and, in some cases, improvements in early survival data indicating the feasibility of the approach.^{51, 52} However, our randomized phase III studies of single-agent chemotherapy regimens failed to confirm these results.^{53, 54} This result probably reflects the lack of efficacy of single-agent chemotherapy for any form of advanced bladder cancer, as well as the confounding impact of the introduction of CT scanning at about the same time as these trials were conducted, thus producing stage migration. Table 4 summarizes phase III studies of neoadjuvant chemotherapy as an adjunct to definitive radiotherapy in muscle-invasive bladder cancer.^{53, 54, 55, 56}

Table 4 Phase III studies of neoadjuvant chemotherapy followed by definitive radiation.

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The largest phase III neoadjuvant study that was carried out by an international cooperative group comprised 976 patients with T2 to T4 bladder cancer who were randomly assigned to receive either three cycles of chemotherapy with cisplatin, methotrexate, and vinblastine (CMV), followed by cystectomy or radiotherapy, or the same treatment without chemotherapy.⁵⁵ When this study was designed, the intent was to secure adequate patient accrual by allowing individual centers to continue their standard practice, and to randomize within patterns of practice—thus, institutions could elect to use radical radiotherapy or cystectomy as definitive treatment. A total of 485 patients underwent cystectomy, 415 were treated with radiotherapy, and 76 received preoperative radiation followed by cystectomy. The 3-year survival difference of 5.5% between neoadjuvant therapy and standard therapy was not significant (55% versus 50%, respectively, P = 0.075), because the trial was powered to detect a 10% increase in absolute overall survival. A later analysis with 7 years of follow-up reported a 15% benefit in overall survival with neoadjuvant CMV. Local regional control was not affected by chemotherapy, although the results indicated a 21% decrease in the risk of metastases, corresponding to an 8% metastasis-free survival benefit with the addition of chemotherapy (P = 0.007). Salvage therapy was given to 36% of patients and included cystectomy, radiation, and intravesical or intravenous chemotherapy. Although the data have been analyzed in many ways, this large study was not powered to identify a significant difference in outcome for patients treated with CMV-radiotherapy versus radiotherapy alone, and, thus, final conclusions regarding this issue cannot be drawn.

Most of the results of individual phase III randomized studies of neoadjuvant chemotherapy have not showed significant outcome differences. A recent meta-analysis from a 2005 Cochrane database review included 3,005 individuals enrolled in 11 randomized trials that compared neoadjuvant chemotherapy with local therapy alone.⁵⁷ Chemotherapy with cisplatin-based combinations conferred a significant benefit in overall survival with a 14% reduction in risk of death, and a 5% absolute benefit at 5 years (from 45% to 50%; HR 0.86, 95% CI 0.77–0.95, P = 0.003). This overall survival benefit was achieved irrespective of the type of surgical or radiotherapy treatment administered, although it should be emphasized that definitive conclusions could not be drawn with regard to the combination of chemotherapy plus radiotherapy versus radiotherapy alone. There was also a significant overall disease-free survival benefit associated with platinum-based combination chemotherapy (HR 0.78, 95% CI 0.71–0.86; P <0.0001), equivalent to a 9% absolute improvement at 5 years, but with the same caveat regarding radiotherapy as definitive treatment. Two other meta-analysis showed that platinum-based combination chemotherapy produced an absolute significant improvement in overall survival of 5–6.5%.^{58, 59}

On the basis of the international trial, the aforementioned meta-analyses, and a Southwest Oncology Group trial where cystectomy was the definitive therapy,⁶⁰ the treatment paradigm for muscle-invasive bladder cancer in North America has shifted away from definitive therapy alone towards the use of neoadjuvant cisplatin-based combination chemotherapy followed by definitive therapy, although this decision has been reached predominantly on data derived from cystectomy series. As indicated in Table 3, the strategies of the RTOG are now based on an acceptance that chemoradiation provides superior local control, and that systemic chemotherapy is needed to overcome occult metastases that exist at first presentation of invasive disease.

What is the optimum approach for invasive bladder cancer?

At present, there is no definitive answer to the question of which combination of modalities comprise the optimum approach for invasive bladder cancer. Critically important factors in defining optimum treatment include the experience of the surgeon planning a cystectomy, the experience of the radiation oncologist, the radiation equipment and available quality assurance for radiation planning, and the extent of pretreatment prognostic information from the pathologist and the clinical staging work-up. As noted previously, there are no data from randomized trials to allow a level 1 evidence comparison between cystectomy and current techniques of radical radiotherapy. In fact, in the modern era, most radiation oncologists seem to have abandoned pure radiotherapy in favor of some form of chemoradiation for the majority of cases of invasive bladder cancer (Table 3). The philosophy of Shipley and colleagues^{41, 42, 46, 48} is, very reasonably, focused on the use of chemoradiation to improve local control, bringing it towards the level afforded by radical surgery, with the caveat that associated systemic chemotherapy (either neoadjuvant or classical adjuvant) should be used to reduce failure from metastatic disease.

At present, a patient with a small, solitary tumor less than 5 cm in size, clinical stage T2–T3a tumor, with no associated carcinoma in situ, no hydronephrosis, no evidence of lymph node or distant metastases, transitional cell histology, and a normally functioning bladder before radiation, is the best candidate for this approach.⁶⁴ Moreover, the patient must be committed to lifelong bladder surveillance with prompt therapy upon recurrence. Additionally, it should be noted that one of the most crucial aspects for the efficacy of radiotherapy-based regimens seems to be extensive TURBT. A suboptimum TURBT may compromise cure, as underscored in one multivariate analysis in which the ability to perform a complete rather than subtotal TURBT was the only independent prognostic factor for long-term survival in the use of combined-modality treatment.²¹

Level 1 evidence shows that neoadjuvant chemotherapy improves outcome when delivered before definitive local treatment, although this level of evidence does not exist specifically with regard to radiotherapy alone as definitive local treatment. Survival trends in favor of neoadjuvant chemotherapy plus radiotherapy, compared with radiotherapy alone, were reported by the International Study⁵⁵ carried out by the European Organisation for Research and Treatment of Cancer, Medical Research Council, NCI Canada, Australian Bladder Cancer Study Group and collaborators, but this trend was not seen in the study conducted by the Danish Cancer Group.⁵⁶ In general, level 2 evidence suggests that chemoradiation yields superior outcomes to radiotherapy alone. The role of neoadjuvant chemotherapy followed by chemoradiation remains unclear, and has not been supported by any level 1 data. Although some contemporary series suggest that a substantial number of patients whose invasive bladder cancers are considerably downsized by chemotherapy alone may be curable by a conservative approach, rather than radical surgery,^{64, 65} the data consist predominantly of phase II trials and, thus, do not constitute level 1 evidence. Of importance, case selection influences outcome heavily, as illustrated by a recent study from the UK,⁶⁶ in which it was shown that only about 50% of patients were fit to receive cisplatin at the doses used in the Canadian study by Coppin and coauthors.⁴⁴ Therefore, a patient with poor kidney function (but medically fit to undergo surgery) may be better served with a cystectomy if cisplatin cannot be used.

Conclusions

To address the continuing paucity of randomized phase III studies comparing chemoradiation with radiation alone, the Trans-Tasman Radiation Oncology Group in Australia and New Zealand is conducting a new trial to compare these treatment regimens. The proposed schedule for the chemoradiation arm is six weekly doses of cisplatin plus radiation to a dose of 64 Gy in 32 fractions delivered over 6.5 weeks. This schedule will be compared with radical radiation alone, with the primary end point being local relapse at 3 years. Another trial from the UK with a similar primary end point is testing standard versus reduced-volume radiotherapy with or without concomitant fluorouracil and mitomycin in patients with muscle-invasive bladder cancer. Results from both trials will not be available for several years. Regrettably, it seems unlikely that level 1 data will ever resolve the controversy surrounding the utility of radical surgery (with or without chemotherapy) compared with the efficacy of any of the schedules of chemoradiation.

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Subject areas under which this article appears: Chemotherapy | Radiotherapy