Researchers in the United Kingdom have found that adding chemotherapy to radiation therapy as a treatment for bladder cancer may reduce the risk of a recurrence more than radiation alone, without causing a substantial increase in side effects.
The combined treatment approach—known as chemoradiation—was tested in 360 patients with muscle-invasive bladder cancer, a potentially deadly form of the disease. Results from the randomized phase III study appeared April 19 in the New England Journal of Medicine.
“The success of this trial could mean that fewer patients need to have their bladders removed,” study co-leader Dr. Nick James, of the University of Birmingham, wrote in an e-mail message. “This approach also provides a viable treatment alternative for frailer patients who are too weak for surgery.”
The authors of an accompanying editorial agreed, calling the trial a “landmark” study.
“These data are really quite compelling,” said one of the editorialists, Dr. William Shipley of Massachusetts General Hospital and Harvard Medical School. Chemoradiation, he continued, can now be regarded as one of several treatment options for patients with muscle-invasive bladder cancer and their physicians to consider.
Preserving the Bladder
In the study, 182 participants were randomly assigned to receive chemotherapy with fluorouracil and mitomycin C in addition to radiation therapy; the other 178 received radiation therapy alone. All participants had muscle-invasive bladder cancer.
Thirty-three percent of the patients who received chemoradiation experienced a relapse in the bladder or in the surrounding tissues within 2 years, compared with 46 percent of those who had radiation therapy alone. The results also showed that, after a median follow-up of about 70 months, the addition of chemotherapy cut the relative risk of invasive disease recurrence by almost half.
Most bladder cancers begin in cells that make up the inner lining of the bladder. In some cases, cancer cells invade the bladder wall and other surrounding tissues. This illustration shows seven stages of bladder cancer, from non-muscle-invasive cancer to muscle-invasive cancer.
There was not a statistically significant difference in overall survival between the chemoradiation and radiation-only groups. More patients in the radiation-only group than in the chemoradiation group had their bladders surgically removed (cystectomy) following a recurrence, and the researchers noted that this increased rate of surgery could make it difficult to determine whether the combination treatment improves survival.
Although the trial did not directly compare chemoradiation with surgical removal of the bladder, the findings add to evidence that a considerable proportion of patients with muscle-invasive bladder cancer can avoid radical surgery for the disease, noted Dr. Bhadrasain Vikram, chief of the Clinical Radiation Oncology Branch of NCI’s Radiation Research Program.
“These trials are hard to do because of the relative rarity of muscle-invasive bladder cancer and—especially in the United States—the conviction of many urologists that removal of the bladder is the preferred treatment whenever possible,” Dr. Vikram added. (Non-muscle-invasive bladder cancers are not life threatening, and minor surgery during cystoscopy is often effective.)
Similar Results Seen in Anal Cancer
The rationale behind testing chemoradiation for bladder cancer was that the chemotherapy would make the radiation therapy more effective, as has been demonstrated in some other cancers. Indeed, the new results mirror the experience of patients with anal cancer, who have been able to avoid the trauma of having the anus removed surgically, noted Dr. Shipley.
When chemotherapy is used to treat bladder cancer in the United States, doctors have traditionally used cisplatin-based combinations rather than fluorouracil and mitomycin C. It will be up to individual physicians to decide which drug to use in a chemoradiation regimen, the editorialists noted.
Regardless of which drugs are used, surgery will remain a critical option for patients treated with an organ-preservation strategy. Patients who have a recurrence after receiving chemoradiation need additional treatment such as surgery; not all patients are candidates for surgery, however.
“Although chemoradiation presents an option for patients who are ineligible for surgery, the current study does not specifically address this patient population,” said Dr. Matthew Milowsky, co-director of the urologic oncology program at UNC Lineberger Comprehensive Cancer Center in Chapel Hill, NC. “This approach is not for all patients, and it is important to appropriately select patients for bladder preservation therapy,” he added.
Matching Patients to Therapies
Future studies will assess potential tumor markers that could help identify candidates for the procedure at the time of diagnosis. One potential marker is a protein called MRE11, which is involved in the cellular response to radiation-induced DNA damage, Dr. Shipley noted.
In the meantime, the new results could increase interest in strategies that aim to preserve the bladder. “Removing the bladder is a major operation with implications for the rest of the patient’s life,” said study co-leader Dr. Robert Huddart, from the Institute of Cancer Research and the Royal Marsden NHS Foundation Trust, in a statement.
In the United States, bladder preservation is underutilized, noted Dr. Howard Sandler, chair of Radiation Oncology at Cedars-Sinai Medical Center. The vast majority of patients who are eligible for surgery get surgery, he said, in part because there are few good studies comparing radiation-based approaches with surgery.
“The take-home message of this study is that patients with muscle-invasive bladder cancer should have a discussion with their physicians about the role of bladder preservation using chemotherapy and radiation therapy,” said Dr. Sandler.
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