In the JournalsPerspective

Chemotherapy ‘vastly underutilized’ in bladder cancer

Neither neoadjuvant nor adjuvant chemotherapy are routinely administered to patients with muscle-invasive bladder cancer despite the potential for both treatments to improve survival, according to findings of a population-based study.

“Patients having surgery for bladder cancer should have chemotherapy, either before or after surgery,” lead researcher Christopher Booth, MD, FRCPC, of Queen’s University Cancer Research Institute in Canada, said in a press release. “Efforts are needed to improve uptake of this treatment, which appears to be vastly underutilized.”

Christopher Booth, MD 

Christopher Booth

Booth and colleagues used the population-based Ontario Cancer Registry to identify 2,944 patients who underwent cystectomy for bladder cancer between 1994 and 2008. They compared the utilization of adjuvant and neoadjuvant chemotherapy among these patients during three time periods: 1994-1998, 1999-2003 and 2004-2008.

The rate of patients who received neoadjuvant chemotherapy remained stable (mean, 4%) during the entire study period. Utilization of adjuvant chemotherapy increased from 16% in 1994-1998 to 18% in 1999-2003, then to 22% in 2004-2008 (P=.001).

Adjuvant chemotherapy was utilized more frequently among patients with T3 or T4 advanced-stage tumors (OR=1.83; 95% CI, 1.38-2.46), those with node-positive disease (OR=8.10; 95% CI, 6.2-10.7) and patients with lymphovascular invasion (OR=1.53; 95% CI, 1.11-2.15). Researchers determined younger patients were more likely to receive either neoadjuvant or adjuvant chemotherapy, as were patients who underwent surgery at a hospital associated with a regional cancer center (neoadjuvant chemotherapy, OR=1.73; 95% CI, 1.18-2.55; adjuvant chemotherapy, OR=1.43; 95% CI, 1.12-1.83).

Among all patients, the rate of 5-year OS was 29% (95% CI, 28%-31%) and the rate of 5-year cancer-specific survival was 33% (95% CI, 31%-35%).

Among patients who received adjuvant chemotherapy, 5-year OS was 29% (95% CI, 25-33) and cancer-specific survival was 28% (95% CI, 24-33). After adjustments for disease and patient characteristics, researchers determined patients who underwent adjuvant chemotherapy demonstrated improved OS (HR=0.71; 95% CI, 0.62-0.81) and cancer-specific survival (HR=0.73; 95% CI, 0.64-0.84) compared with those who did not.

“Results from our study demonstrate that chemotherapy given after surgery improves patient survival — probably on the same order of magnitude as chemotherapy before surgery,” Booth said.

Among patients who underwent neoadjuvant chemotherapy, 5-year OS was 25% (95% CI, 17-34) and cancer-specific survival was 28% (95% CI, 18-39). The 5-year OS rate was considerably lower than the 49% to 57% rate reported in prior trials, but selection and referral biases, the association between greater cystectomy case volumes and better outcomes, and differences in surgical techniques may have contributed to the difference, according to the researchers.

“Given the potential for perioperative chemotherapy to improve patient outcomes, further efforts are needed to understand reasons for underutilization,” Booth and colleagues wrote. “The comparatively poor outcomes of patients in routine practice compared with survival reported in clinical trials suggest a substantial efficacy-effectiveness gap that requires further attention to improve the outcomes of patients with muscle-invasive bladder cancer in the general population.”

Disclosure: The researchers report no relevant financial disclosures.

Daniel P.  Petrylak, MD

Daniel P. Petrylak

  • Despite two randomized trials that demonstrated a survival benefit for neoadjuvant chemotherapy, there has been considerable difficulty in its adoption as a standard of care for muscle-invasive bladder cancer. The data supporting the use of adjuvant chemotherapy is less robust. A recent randomized trial by the European Organisation for Research and Treatment of Cancer demonstrated a significant improvement in PFS but not OS with immediate cisplatin-based adjuvant chemotherapy when compared with deferred treatment. Although there has been some improvement in the number of patients who are offered and subsequently receive neoadjuvant therapy, a recent analysis of patients treated in Ontario after changes in practice guidelines reported that only 23% of patients were offered neoadjuvant treatment, and 18% actually received it.
    To determine how the patterns of perioperative therapy have changed in Ontario, Booth and colleagues examined the records of 3,879 patients who underwent cystectomy for bladder cancer. The patients were analyzed by time periods grouped by date of cystectomy: 1994 to 1998, 1999 to 2003, and 2004-2008. The percentage of patients who received adjuvant therapy increased steadily from 16% in the first time period to 18% in the second time period and 22% in the third time period, whereas the percentage of patients who received neoadjuvant chemotherapy varied from 5% in the first time period to 3% in the second time period and 6% in the third time period. Researchers reported comparable rates of 5-year OS (25% vs 29%) and cancer-specific survival (28% vs. 28%) for neoadjuvant and adjuvant chemotherapy. The 5-year survival was lower than that the 52% projected in the SWOG neoadjuvant chemotherapy trial; this may be reflective of the medical condition of the overall population, and the fact that patients could have received non-cisplatin–containing regimens. An adjusted analysis demonstrated a significant improvement in OS for those treated with adjuvant therapy (HR=0.71).
    In the time period before the publication of the SWOG data in 2003, retrospective population-based studies of perioperative chemotherapy for muscle-invasive bladder cancer demonstrated a predominance of patients who received adjuvant therapy. This study clearly indicated that the positive results of neoadjuvant chemotherapy have not changed clinical practice and, in fact, there has been a continued shift in perioperative treatment toward adjuvant therapy.
    Administration of treatment based on evidence is essential not only to patient care, but also to clinical trial design and implementation. If the major argument for administering adjuvant therapy instead of neoadjuvant therapy is to select only those patients who are at high risk and not expose patients to chemotherapy unnecessarily, perhaps trials that incorporate active and less toxic agents — such as immune checkpoint inhibitors — in the neoadjuvant setting will help to reverse this trend.
    • Daniel P. Petrylak, MD
    • HemOnc Today Editorial Board member
      Yale School of Medicine
  • Disclosures: Petrylak reports no relevant financial disclosures.