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Journal of Clinical Oncology, Vol 22, No 13 (July 1), 2004: pp. 2540-2545
© 2004 American Society of Clinical Oncology.
DOI: 10.1200/JCO.2004.10.070
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Combined-Modality Therapy With Gemcitabine and Radiotherapy As a Bladder Preservation Strategy: Results of a Phase I Trial

Elizabeth Kent, Howard Sandler, James Montie, Cheryl Lee, Joseph Herman, Peg Esper, Judith Fardig, David C. Smith

From the Departments of Internal Medicine, Radiation Oncology, and Urology of the University of Michigan School of Medicine and the University of Michigan, Comprehensive Cancer Center

Address reprint requests to David C. Smith, MD, 7302 CCGC 0946, 1500 E Medical Center Dr, Ann Arbor, MI 48109; e-mail: dcsmith{at}umich.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Authors' Disclosures of...
 REFERENCES
 
PURPOSE: We conducted a phase I trial of gemcitabine given twice weekly with concurrent radiotherapy in patients with muscle-invasive bladder cancer.

PATIENTS AND METHODS: Eligible patients underwent maximal transurethral resection of their bladder tumors followed by twice-weekly infusion of gemcitabine with 2 Gy/d concurrent radiotherapy to the bladder, for a total of 60 Gy over 6 weeks. The starting dose of gemcitabine was 10 mg/m2 with subsequent dose levels of 20, 27, 30, and 33 mg/m2. The primary end point was the determination of the maximum-tolerated dose (MTD) of twice weekly gemcitabine with concurrent radiotherapy. Secondary end points included assessment of toxicity associated with combined-modality therapy and initial assessment of the rate of bladder preservation.

RESULTS: Twenty-four patients were enrolled and 23 were assessable for toxicity and response. No significant toxicity was demonstrated at the 10 or 20 mg/m2 twice-weekly doses. Dose-limiting toxicity (DLT) occurred in two of three patients treated at 33 mg/m2. Intermediate dose levels of 27 and 30 mg/m2 were then evaluated. The MTD of gemcitabine was 27 mg/m2. The DLT was systemic, manifested as an elevation in liver function tests, malaise, and edema. Fifteen of 23 patients (65%) are alive with bladders intact and no evidence of recurrent disease at a median follow-up of 43 months.

CONCLUSION: Twice-weekly gemcitabine with concurrent radiotherapy at 2 Gy/d to a total dose of 60 Gy is well-tolerated. The MTD of gemcitabine is 27 mg/m2. There is a high rate of bladder preservation in this selected group of patients.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Authors' Disclosures of...
 REFERENCES
 
Muscle-invasive bladder cancer is an increasing cause of cancer morbidity and mortality, estimated to result in 12,600 deaths in the year 2002.1 In the United States, radical cystectomy with pelvic lymph node dissection has long been the standard of care for this disease, with long-term survival rates near 50%.2-4 Outcome is strongly dependent on pathologic stage, with only 33% long-term survival for pT4, compared with 72% for pT2.3 The procedure itself involves removal of the bladder, the surrounding structures (including the prostate or uterus), and the regional lymph nodes; and urinary diversion. Accordingly, radical cystectomy often results in considerable morbidity, including incontinence and impotence.3,4

Because of this potential morbidity, organ preservation—which has been successful in cancers such as breast cancer, soft tissue sarcomas of the extremities, and laryngeal carcinoma—has been the subject of recent investigation. Approaches have included maximal transurethral resection (TURBT) of the tumor combined with radiotherapy, chemotherapy, or both. Results with radiotherapy alone are suboptimal.2,5-7 Chemotherapy alone results in overall survival rates equivalent to cystectomy alone, but only 18% to 33% of patients are able to keep their bladder for 5 years.8-10 A more promising approach using concurrent chemotherapy and radiation therapy has improved bladder-intact disease-free survival, without evident compromise of overall survival.11-20 Stage again was a powerful predictor of outcome. For instance, in recently reported long-term results of combined-modality therapy, 56% of clinical T2 patients were alive at 5 years, as compared with 17% of patients with clinical T4 disease.20 Each of these trials used cisplatin, chosen both for its cytotoxic activity against transitional cell carcinoma and for its radiosensitizing properties. Unfortunately, this agent can also have significant toxicity, limiting its utility. In RTOG 85-12, for example, only 30 of 42 assessable patients were able to complete the entire therapy per protocol.

Gemcitabine is a nucleoside analog with promising activity in transitional cell carcinoma. As a single agent in phase II trials in metastatic bladder cancer, it has a response rate 20% to 28%.21-23 More recently, it has been used in combination with agents such as cisplatin, carboplatin, and paclitaxel, with response rates approaching those reported for combination methotrexate, vinblastine, doxorubicin, and cisplatin.24-27 In addition, gemcitabine has significant activity as a radiosensitizer in both in vitro and in human studies.28,29 This activity is noted at subcytotoxic doses, and the mechanism is thought to be through depletion of deoxyribonucleoside triphosphate pools, particularly deoxyadenosine triphosphate (dATP).30,31 Several phase I and II trials have used gemcitabine combined with radiation therapy, with varying results. Although two phase I trials (one in head and neck cancer and one in non–small-cell lung cancer) resulted in excessive toxicity.32,33 subsequent investigators, using doses ranging from 150 to 450 mg/m2/wk in combination with radiotherapy, have had more success.34 Furthermore, based on preclinical studies demonstrating that even lower doses of gemcitabine effectively radiosensitize cells for up to 72 hours,35,36 several phase I trials in lung and pancreatic cancers have used lower doses of gemcitabine twice weekly.37,38

In an effort to allow good-risk bladder cancer patients to retain their bladder, and noting the promise of combined gemcitabine and radiation in other tumor types, we elected to perform a phase I dose-finding trial of twice-weekly gemcitabine and concurrent radiation in patients with muscle-invasive bladder cancer.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 Authors' Disclosures of...
 REFERENCES
 
Patient Eligibility
Eligible patients had histologically confirmed muscle-invasive transitional cell carcinoma that was clinical stage T2 or T3 and amenable to transurethral resection. All patients were candidates for cystectomy and had absolute neutrophil count (ANC) ≥ 1,500/µL, platelets ≥ 100,000/µL; creatinine ≤ 2.0, bilirubin ≤ 3 times the institutional upper limit of normal, AST ≤ 4 institutional upper limit of normal, Eastern Cooperative Oncology Group performance status ≤ 1, and no prior radiotherapy or systemic therapy for transitional cell carcinoma. Patients with adenomatous or squamous differentiation of their tumors were eligible. Imaging studies (abdominal/pelvic computed tomography [CT] scan and chest radiograph) were performed before initiation of therapy in order to rule out any evidence of locally advanced or metastatic disease. All patients were assessed by the senior urologic, medical, and radiation oncologist before participation to ensure compliance with the eligibility criteria. The study was reviewed and approved by the University of Michigan Medical School institutional review board. Patients were informed of the investigational nature of the study and provided written informed consent before registration onto the study.

Study Design and Treatment
This trial was designed as a phase I dose-finding study to determine the maximum-tolerated dose (MTD) of twice-weekly gemcitabine, administered concurrently with radiation therapy to the bladder. Dose-limiting toxicity (DLT) was defined as grade 4 neutropenia or thrombocytopenia, febrile neutropenia, or any grade ≥ 3 nonhematologic toxicity, except for nausea or vomiting or alopecia, according to Southwest Oncology Group toxicity criteria. Before study entry, patients underwent TURBT with maximal debulking of their bladder tumor at the University of Michigan. All patients had undergone a TURBT before being seen by our group to establish the diagnosis. After 4 to 5 weeks to allow for adequate healing, patients were assigned a dose level for twice-weekly gemcitabine. Gemcitabine was administered with standard antiemetics (prochlorperazine or thiethylperazine) on Monday and Thursday as a 30-minute infusion for 6 weeks, immediately before radiation therapy. Radiation therapy was administered to the bladder using CT-planned three dimensional-conformal techniques for 60 Gy total, 2 Gy/d, for a total of 6 weeks. The planning target volume included the gross tumor volume (bladder plus any extravesical tumor) with a 1 cm expansion. Patients were simulated and treated with the bladder empty. Three patients were enrolled at each dose level, with the initial dose of gemcitabine being 10 mg/m2. Subsequent planned dose levels were 20 mg/m2, 33 mg/m2, 50 mg/m2, and 60 mg/m2. These doses were based on the available preclinical data and ongoing phase I trials in other diseases.37,38 All three patients at a given dose level were observed for at least 3 months following the completion of therapy before patients were enrolled at the next dose level. Dose escalation proceeded only after at least three patients at each dose level had completed the full 6 weeks of therapy without encountering DLT, and any toxicity had resolved to ≤ grade 2. If none of the patients treated at a given dose level had DLT, the next cohort of patients were enrolled at the next dose level. If at least two patients enrolled at any dose level encountered DLT, the MTD was considered to be exceeded, dose escalation ceased, and three patients enrolled at the preceding dose level. If one of three patients had a DLT, then three additional patients were enrolled at that dose level. If fewer than two of the six patients treated at the lower dose level had DLT, than an intermediate dose was assigned to more accurately define the MTD. Doses adjustments were based on weekly ANC and platelet counts, taken not more than 36 hours before infusion of gemcitabine, and clinical assessment of nonhematologic toxicities. Doses were held for ANC less than 1,000/µL, platelet count less than 50,000/µL, and grade ≥ 3 nonhematologic toxicity, except for controlled diarrhea or nausea and vomiting. No prophylactic cytokine treatment was used.

Assessability, Toxicity, and Response Criteria
Pretreatment evaluation included complete history and physical examination; performance status assessment; complete blood count; electrolytes; blood urea nitrogen; serum creatinine; liver function tests; total protein, albumin, magnesium, and serum calcium; and appropriate imaging studies to assess extent of disease. During treatment, patients were seen weekly in the Department of Radiation Oncology, at which time their weight was recorded and toxicity was monitored using the Southwestern Oncology Group toxicity criteria. Complete blood counts, including differential and platelets, were performed twice weekly before each administration of gemcitabine. Every 3 weeks, patients were seen in the medical oncology clinic, where full physical examination, monitoring of toxicity, and laboratory evaluation, including complete blood count, electrolytes, liver function, and kidney function, were performed. At 10 weeks, patients underwent repeat transurethrol resection of the site of the original tumor and urine cytology, as well as CT scan of the pelvis and chest radiograph.

Response, though not a primary end point of this trial, was monitored with cystoscopy, cytology, and imaging studies. Complete response was defined as complete disappearance of all measurable and evaluable disease, confirmed by cystoscopy, biopsy, and urine cytology. Patients with any evidence of residual or recurrent tumor in the bladder were deemed to have experienced treatment failure; for such patients, cystectomy was advised. Duration of response was defined as the period of time from documentation of response until evidence of disease recurrence. Survival was the time from study entry until patient death.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 Authors' Disclosures of...
 REFERENCES
 
Patient Characteristics
Twenty-four patients were registered and found to be eligible for the trial (Table 1). All patients were male, and all had Eastern Cooperative Oncology Group performance status 0-1. Median age was 62 years (range, 46 to 83 years). All patients had T2 lesions that were amenable to TURBT. In seven patients, residual tumor was suspected to remain after maximal transurethral resection, as determined by the attending urologist. The remaining 17 patients had complete resection of their tumors. All 24 patients had high-grade transitional cell carcinoma. One each had focal squamous differentiation, focal sarcomatoid differentiation, and gland-like formation. Seven patients had associated carcinoma-in-situ (CIS). Twenty-three patients were assessable for toxicity and response. One patient, having undergone a partial cystectomy, declined further therapy and has remained without evidence of disease.


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  		Table 1. Patient Characteristics

 
Toxicity
The toxicities seen in this trial are summarized in Table 2. None of the patients enrolled at 10 mg/m2 twice weekly experienced DLT. None of the original three patients at 20 mg/m2 experienced DLT, although one experienced transient grade 3 neutropenia. Two of the next three patients, enrolled at 33 mg/m2, developed DLTs; one patient had grade 4 diarrhea due to a radiation stricture that eventually resolved, and one was hospitalized with transient grade 3 edema, diarrhea, weakness and coagulopathy. Thus, three more patients were treated with 20 mg/m2; one of these developed a grade 3 elevation of his liver transaminases. Three patients were then enrolled at 27 mg/m2; one developed mild radiation cystitis with a stricture that required dilation; none had dose-limiting toxicities. Six patients were subsequently enrolled at 30 mg/m2. Two of the six patients at this dose also developed transient asymptomatic grade 3 elevation of liver transaminases. One also experienced dehydration resulting in prerenal azotemia with asthenia and was hospitalized. Two additional patients were then enrolled at 27 mg/m2. Neither had any dose limiting toxicities. No patients developed life-threatening complications. There has been one significant late complication. The patient mentioned with radiation cystitis has had persistent hematuria unresponsive to conservative measures. This has responded however, to therapy with hyperbaric oxygen.


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  		Table 2. Dose Escalation and Toxicities

 
Response
Twenty-one of 23 assessable patients achieved complete response as measured by the absence of persistent or recurrent disease at the first cystoscopy following therapy and negative urine cytology. One of the patients who failed to achieve a complete response refused further therapy and died as a result of metastatic disease 18.5 months after completing the therapy. The other underwent cystectomy and remains without evidence of recurrent disease. Three patients have developed recurrent superficial disease within the bladder, one each at 4, 6, and 8 months post-therapy. Two have undergone cystectomy, and the third chose to be treated with bacille Calmette-Guerin. All three remain without evidence of disease post salvage therapy. All patients who underwent salvage cystectomy were able to have an ileal neobladder constructed.

Three of the patients with initial complete responses have died. One presented with widespread metastatic disease including brain lesions less than 3 months after having no evidence of disease on routine computed tomography and cystoscopy. One patient developed a primary lung cancer 53 months after completing therapy. This patient had no evidence of disease recurrence within his bladder and retained his bladder with normal function for 4.5 years after entering the study. The third patient developed an upper-tract transitional cell carcinoma and died of metastatic disease. It was unclear whether the metastases originated from the upper tract lesion, which was initially a low-grade carcinoma, or from his bladder primary, which was a high-grade lesion. Another patient has developed a Gleason score 7 prostate cancer. None of these second maligancies are thought to attributable to this therapy.

Eighteen of the 23 assessable patients are alive and in follow-up (one lost to follow-up), with a median survival of 43 months from completion of therapy. Sixteen patients (70%) are alive with their bladders intact at a median follow-up of 40.5 months (range, 11 months to 6 years) from completion of therapy. Fifteen patients (65%) are alive with bladders intact, no evidence of recurrence at any site, and no grade 3 or 4 toxicity at a median time of 43 months from study entry.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
Authors' Disclosures of...
 REFERENCES
 
Currently, patients with muscle-invasive transitional cell carcinoma have limited options for bladder preservation. Regardless of clinical stage, radical cystectomy remains the standard approach for the majority of these patients. As noted, however, patients with lower clinical stage tend to have better outcome, with long-term survival rates greater than 70%.3 For these patients, preservation of the bladder and its function, with adequate eradication of tumor, could markedly improve long-term quality of life.

Several groups have studied combined-modality therapy with the aim of selective organ preservation. Four trials have been performed using platinum derivatives in combination with radiotherapy without induction chemotherapy.11-14 Performed in patients with clinical stages T2-T4a, 5-year tumor-free, bladder intact survival was approximately 40%. Several additional trials examined the addition of induction chemotherapy with MCV before the concurrent cisplatin and radiotherapy.16-19 Similar 5-year tumor-free bladder-intact survival rates were noted, with no advantage to induction chemotherapy in phase III evaluation. The survival data for patients requiring salvage cystectomy, defined as cystectomy for either residual or recurrent tumor, was not specifically available for each of these studies. Toxicity, when reported, was considerable, both for those with and without induction chemotherapy. Specifically, grades 3 and 4 hematologic and gastrointestinal toxicity were noted in up to 15% of patients and often resulted in decreased completion rates.

In this study, gemcitabine was chosen both because of its potent radiosensitizing properties and because of its more favorable toxicity profile. The toxicity in our patient population was much less than anticipated. Only one patient has experienced radiation cystitis. Hematologic toxicity was minimal. The most interesting finding, and the most unexpected, was the transient liver enzyme elevation, which proved to be dose limiting. This has not been seen in previously published studies involving combined radiotherapy and gemcitabine, either in the weekly39-42 or twice-weekly dosing.37,38 Even in the study by McGinn et al,43 in which full doses of gemcitabine (1,000 mg/m2/wk) were combined with escalating doses of radiotherapy in pancreatic cancer, no hepatic toxicity was reported. Concurrent medications did not appear to play a role. The reason for this unexpected toxicity is unclear.

The radiotherapy used in this trial was delivered with conformal techniques to the bladder plus any extravesical tumor with an appropriate margin for set-up uncertainties. No prophylactic nodal irradiation was used and, to date, there have been no isolated pelvic lymph node recurrences. The restricted radiotherapy volume was chosen for two reasons. There was concern regarding the potential toxicity of combining gemcitabine and radiotherapy to a large pelvic region, as would be required for full pelvic lymph node treatment. In addition, the dose to small bowel and prostate was limited to facilitate salvage surgical management and to allow neobladder reconstruction, if necessary.

Although the trial was not designed to evaluate response as a primary end point, the fact that 65% of the patients have remained disease-free with bladders intact at a median of 43 months is encouraging. It is not possible to know whether some of these patients would have had the same outcome with TURBT alone or in combination with radiotherapy. In general, patients who entered this trial had a good prognosis, with limited disease amenable to TURBT. In fact, although entry criteria allowed enrollment of patients with T3 disease, because of competing protocols at our institution, all patients entered onto this study had T2 disease. Patient selection is undoubtedly a critical factor in the success of bladder-preservation strategies. It seems unlikely, however, that the overall success of the approach is due to either resection alone or the combination with radiotherapy, given the historical data from various trials. It is also uncertain whether the overall survival rate would have been higher in this population if patients had undergone radical cystectomy. The patients enrolled on this trial were largely spared, however, the risks of surgery and the inconvenience of dealing with urostomy devices and the training of neobladders.

Further evaluation of this approach should include measurement of the effect of therapy on quality of life. Phase II trials to determine the overall rate of bladder preservation are clearly warranted. This approach may also be applicable in patients who are not candidates for radical surgery because of comorbid conditions, and this population should be studied separately. If these studies fulfill the potential indicated by this study, it may possible for a subset of patients with bladder cancer to be effectively treated without the potentially debilitating effects of radical surgery.


   Authors' Disclosures of Potential Conflicts of Interest
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Authors' Disclosures of...
REFERENCES
 
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Performed contract work within the last 2 years: David C. Smith, Eli Lilly.


   NOTES
 
Supported in part by 2P30 CA 46592-14 from the National Cancer Institute and the National Institutes of Health and a grant from Eli Lilly and Company.

Authors' disclosures of potential conflicts of interest are found at the end of this article.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Authors' Disclosures of...
 REFERENCES
 
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Submitted October 8, 2003; accepted April 7, 2004.




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