68 patients were enrolled between June 2000 and September 2005. Sixty-three patients had biopsy proven muscle-invasive transitional cell carcinoma of the bladder. Five patients had variant or mixed histologies of urothelial carcinoma (3 with predominant squamous cell carcinoma, 2 with adenocarcinoma). Median age was 61.5 years (range: 29−83), median performance status was 1 (range 0−2), and 90% of participants were Caucasian. The patient characteristics and treatment administered are summarized in and respectively.
Arm I of the study enrolled 31 patients, and 22 were evaluable for response. Nine patients were not evaluable for the primary endpoint. One refused cystectomy, but remains free of disease more than 3 years since completing chemotherapy. Four were removed from study due to toxicity. One developed urinary obstruction from nephrolithiasis resulting in a delay in treatment after one cycle of therapy. One patient suffered a vesicorectal fistula, small bowel obstruction and urosepsis after one cycle. Two additional patients (following 1 and 2 cycles respectively) experienced a >2 week delay in treatment from dehydration, low blood counts and one of the two experienced urosepsis. There were 4 preoperative deaths all occurring during the first cycle of chemotherapy on this arm of the study. One patient suffered a cardiac arrest from previously unrecognized three-vessel coronary artery disease, one had apparent bowel obstruction due to a prior colon resection then became neutropenic, one experienced a bowel obstruction after one cycle and at the time of surgery was found to have peritoneal carcinomatosis not detected by baseline imaging, and the fourth developed a strangulated hernia and suffered complications following his bowel surgery with renal failure and failure to wean from mechanical ventilation. There were two post-cystectomy deaths. One patient suffered multiorgan failure postoperatively in the setting of Crohn's disease and ankylosing spondylitis. A second patient died of pseudomembranous enterocolitis during his recovery from surgery. Due to the mortality rate during chemotherapy, we elected to close this arm prior to reaching the planned enrollment goal.
Arm II enrolled 37 patients and 29 were evaluable for response. Two patients received only three cycles of therapy before proceeding to radical cystectomy. No significant toxicity was recorded and no reason for a shortened course was provided for either patient. Of the eight patients not evaluable for response, three were found to have metastatic disease which became apparent during their neoadjuvant therapy. This manifested as sclerosis of bone lesions which in retrospect were actually present but not reported on baseline CT scans. One patient had an acute myocardial infarction necessitating coronary bypass surgery during cycle 3, one was removed due to protocol noncompliance and one developed persistent peripheral neuropathy after cycle 3 of therapy and was treated off study with further neoadjuvant therapy. Two patients had a decline in their performance status necessitating > 2 week delay in treatment (one due to dehydration during cycle 3 and another to hematuria from the tumor during cycle 1). An additional patient developed a recurrent arterial femoral thrombus due to a dissection at the site of a prior arterial bypass graft and completed only 4 cycles of therapy. She went on to radical cystectomy. The only death on this arm of the study occurred in a patient who had an intracranial hemorrhage with grade 4 thrombocytopenia following the sixth cycle of therapy. As both of these patients were deemed resectable, they are included in the analysis for response.
Toxicity is summarized in . All patients treated were included in the analysis for toxicity. Overall, myelosuppression and neutropenia were the most common grade 3−4 toxicities. Febrile neutropenia was rare with only 3 events (3 events/253 cycles = 1 %) all of which occurred in patients enrolled on arm I. No pretreatment characteristic appeared to predict for development of toxicity.
In arm I, a total of 22 patients were evaluable for response (defined as ability to assess pathologic response). Seven had a pathologic complete response at time of radical cystectomy. Thus the response rate was 32% of evaluable patients and 22% by intent to treat. An additional patient had no residual invasive tumor but was found to have carcinoma in-situ.
In arm II, a total of 29 patients were evaluable for response. 24 were considered resectable following neoadjuvant therapy (83% of evaluable, 65% by intent to treat). Of the 24 patients, 21 underwent cystectomy. Five patients had a pT0, 2 patients had pTis and the remaining 14 patients had residual invasive bladder cancer. Of the three patients deemed resectable that did not proceed to surgery, one was the patient who suffered an intracranial hemorrhage and expired after completing six cycles of chemotherapy. One had an excellent response by radiographic imaging but ultimately was felt to be too obese to proceed with surgery. He received combination chemotherapy and radiation therapy for definitive management in lieu of surgery. Following bariatric surgery and subsequent weight loss, he underwent radical cystectomy due to cytologic evidence of persistent bladder cancer. The third patient refused surgery and received salvage radiation therapy to a minimal residual urethral mass.
Although survival was not the primary endpoint of either arm of the study, data is available for the majority of the patients. Median overall survival in all patients on arm I was 18.8 months (range: 0.5 to 83.2 months). Median progression free survival in the 23 patients with data available was 35.3 months (range: 4.2 − 83.2 months). In arm II the median survival in all patients was 28.5 months (range: 1.5 − 77.6 months). Median progression free survival on arm II was 17 months (range: 2 − 77.6 months) in the 32 patients with available data. Twenty-one patients (31%) remain alive and disease free (10 in arm I, 11 in arm II) at a median followup of 58.7 months.