Which Is Best Neoadjuvant Chemo in Bladder Cancer?

Kristin Jenkins

September 10, 2018

For patients with bladder cancer, chemotherapy before surgery improves survival when compared with surgery alone. But there is a question over which neoadjuvant chemotherapy (NAC) therapy should be used.

Although gemcitabine with cisplatin (GC) has become a standard NAC regimen, some institutions are adopting a dose-dense combination of methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVAC).

A new study shows that this less-frequently-used ddMVAC combination appears to be associated with significantly higher rates of complete response and disease downstaging in patients undergoing radical cystectomy for muscle-invasive bladder cancer (MIBC).

The study, led by Scott M. Gilbert, MD, MS, from the H. Lee Moffitt Cancer Center and Research Institute in Tampa, Florida, was published online August 30 in JAMA Oncology.

The cross-sectional analysis of more than 1000 patients who underwent cystectomy compared patients who received ddMVAC to those treated with other regimens or with cystectomy alone.

Among 46 patients who received an average of 3.3 cycles of ddMVAC before surgery, 19 (41.3%) had a complete response.

By comparison, of the 204 patients who received an average of 3.7 cycles of standard-of-care GC, there was a complete response in 50 (24.5%).

"Although gemcitabine with cisplatin [GC] is the most frequently prescribed neoadjuvant chemotherapy regimen for patients with muscle-invasive bladder cancer, for eligible patients, treatment with dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin [ddMVAC] may lead to better outcomes," the authors write.

"These data highlight and suggest the need to further investigate ddMVAC vs standard NAC in a prospective, randomized fashion."

Study Details

For the study, the patient cohort was assembled from a registry of 1186 patients who underwent cystectomy at the Moffitt Cancer Center during the 10-year period from January 1, 2007, to May 31, 2017.

Of the 824 patients with MIBC, 332 (40%) were treated with NAC. Patients who did not receive NAC served as controls. Overall survival time was measured from the time of cystectomy to the last follow-up or death from any cause.

The study showed that in 32 patients treated with gemcitabine-carboplatin, a NAC regimen commonly used in cases of renal insufficiency, 9.4% (3 patients) had a complete response. This was lower than the complete response rate of 10.7% for cystectomy alone, raising questions about the role of gemcitabine-carboplatin in advanced bladder cancer, the researchers said.

"[N]eo-adjuvant gemcitabine-carboplatin appears essentially ineffective. Complete response rates were low, and more concerning still, the adjusted risk of death was significantly higher than for the reference gemcitabine-cisplatin group (HR [hazard ratio], 2.0)," they note.

The analysis also showed a greater likelihood of downstaging in patients treated with ddMVAC (19 patients [52.2%]) than in those treated with GC (50 patients [41.3%]) or with gemcitabine and carboplatin (10 patients [27.0%]). The researchers defined downstaging as any decrease in stage or complete pathologic response using the TNM malignant tumor classification pT0N0 or ypT0N0.

While neoadjuvant ddMVAC was associated with longer survival intervals and a lower risk for death than the other NAC regimens, this benefit did not reach statistical significance (HR, 0.44; P = .16). Still, the researchers emphasized that the survival differences were large enough to be clinically relevant.

"[W]e were able to demonstrate a direct and significant relationship between ypT0N0 downstaging and survival, adding plausibility to the survival benefit of ddMVAC compared with gemcitabine-cisplatin…. Larger comparative studies are needed to definitively answer questions regarding survival," they conclude.

Previous Studies Show Benefit of NAC

The investigators cite several studies that highlight the benefit of neoadjuvant chemotherapy in patients with bladder cancer.

A 2003 study showed that NAC before cystectomy was associated with a 6% survival benefit at 10 years. This landmark trial comparing neoadjuvant MVAC to cystectomy alone reported significant improvement in complete pathologic response (38% vs 15%; P < .001) and median overall survival (77 vs 46 months; P = .05) with MVAC.

However, that 2003 trial also showed that more than 50% of patients treated with MVAC experienced serious toxic effects including myelosuppression and mucositis. "These adverse events have limited the widespread use of MVAC to date," Gilbert and colleagues commented.

For this reason, GC has been recommended as first-line therapy by the American Urological Association/ Society of Urologic Oncology, the National Comprehensive Cancer Network, and the European Association of Urology, the researchers note. Despite this, adoption rates for GC as the standard of care have been modest, they said.

More Research Is Needed

When asked to comment, David J. McConkey, PhD, director of Johns Hopkins Greenberg Bladder Cancer Institute in Baltimore, Maryland, agreed that more research is needed. Like the authors, he noted the low number of patients in the ddMVAC group despite the high number of patients in the cohort overall.

"This study has produced some provocative results which might be leading us in a particular direction, but the findings are not conclusive so the jury is still out. What we need is a real head-to head comparison under prospective conditions," he added.

McConkey predicted that ongoing research focusing on the impact of NAC on the immune microenvironment will be more effective than studies looking at the superiority of one agent over another in terms of survival.

"Biomarkers will make it possible to identify subgroups of patients who will benefit from NAC," McConkey told Medscape Medical News. "If one regimen provides more impact on the immune microenvironment, there will be some very exciting results, so stay tuned," he said.

He was referring to the Southwest Oncology Group's (SWOG)-S1314 trial, which is looking at tumor biomarkers using a computational method called Co-eXpression ExtrapolatioN (COXEN).

In previous work, a research team led by McConkey — who was then at the University of Texas MD Anderson Cancer Center in Houston — found that gene expression profiling can be used to predict sensitivity and resistance of different urothelial subtypes to conventional cisplatin-based combination chemotherapy. That 2016 study showed that the basal subtype was associated with better survival, while the p53-like subtype was associated with bone metastases and chemoresistant disease.

We can no longer think of urothelial cancer as a single disease Dr David McConkey


"We can no longer think of urothelial cancer as a single disease," McConkey and colleagues wrote. "Gene expression profiling identifies subtypes of urothelial cancer that differ in their natural history and sensitivity to chemotherapy."

Another expert approached for comment, Jean Heather Hoffman-Censits, MD, associate professor of oncology at Johns Hopkins School of Medicine in Baltimore, Maryland, agreed.

"For patients undergoing neoadjuvant chemotherapy, we have learned that urothelial bladder tumors with defects in DNA damage repair mechanisms are more responsive to chemotherapy," she told Medscape Medical News.

Studies to evaluate prospectively novel treatment paradigms based on this biomarker are ongoing, she noted. "These and other individualized novel therapies based on tumor characteristics give us hope that better outcomes for our patients with bladder cancer are on the horizon."

Although the phase 2 COXEN trial is not designed to evaluate a difference in efficacy between CG and accelerated MVAC (aMVAC), it will "provide prospective assessment of the toxicity and completion rates of these regimens in a neoadjuvant setting," Hoffman-Censits predicted.

The ongoing phase 3 European VESPER study, which is designed to evaluate progression-free survival and tolerability using GC or aMVAC in the perioperative setting, "will also be informative," she said.

Like the study authors, Hoffman-Censits noted that the current study is one of several retrospective studies comparing the efficacy of neoadjuvant aMVAC or traditional MVAC to GC.

"Though informative and hypothesis generating, these studies are all limited by their retrospective nature," she said.

Several other prospective neoadjuvant studies of aMVAC have shown it to be a safe, efficient, and effective regimen, with downstaging rates commensurate with those originally reported with traditional multiday MVAC, she pointed out.

The presence of lymphovascular invasion, hydronephrosis, and variant histology are also important factors in interpreting chemotherapy response in the neoadjuvant setting, even though they are not always reported, Hoffman-Censits said.

In the current study, as well as in a previous report, patients receiving aMVAC were slightly younger than those receiving gemcitabine and cisplatin. This could reflect selection bias, she suggested.

She also noted that 91.3% of patients receiving ddMVAC and 73.7% of patients receiving GC received more than three cycles of chemotherapy. "Whether this is an indication of treatment tolerability, patient selection, or other unmeasured factors is not known. The ongoing SWOG-1314 COXEN trial may enlighten our field to some of these findings." 

The current study showed that ddMVAC treatment — from initiation of NAC to the date of surgery—took less time than other NAC regimens, letting patients complete their global treatment more quickly. "This may be relevant in bladder cancer, where time to definitive local therapy may impact outcome," said Hoffman-Censits.

The finding that neoadjuvant gemcitabine and carboplatin was no more effective than cystectomy alone was not a surprise, she added.

"Achievement of pathologic complete response in invasive bladder cancer is predicated upon adequate preoperative tumor staging with transurethral resection of bladder tumor (TURBT) and effective chemotherapy. We have long known that for urothelial cancer, carboplatin-based regimens are inferior to cisplatin regimens. Outside of a clinical trial, our field does not endorse preoperative carboplatin chemotherapy, which not only delays the potentially curative radical cystectomy but can add potential toxicity which may further delay or complicate surgery," she commented.  

Hoffman-Censits pointed out that only 40% of the patients in the study seen at the tertiary referral center received neoadjuvant chemotherapy, and 31% received regimens that were definitely cisplatin based. "While these statistics are vastly improved from reports of neoadjuvant chemotherapy utilization a decade ago, we still have far to go," she said.

"Preoperative cisplatin based chemotherapy is supported by level 1 data with overall survival improvement compared to surgery alone," she said. "Best care of patients with invasive bladder cancer employs a multidisciplinary approach where discussion and assessment for multimodality therapy occur in a timely fashion, and where standard evidence-based chemotherapy regimens are delivered." 

The study also highlights that for up to 50% of patients with invasive urothelial cancer who are not candidates for cisplatin chemotherapy, novel effective and tolerable perioperative regimens are needed, Hoffman-Censits said.

The current study was funded by the National Cancer Institute. Gilbert and the study coauthors have disclosed no relevant financial relationships. McConkey disclosed financial relationships with Apocell Inc and Astra-Zeneca, and Hoffman-Censits reported a financial relationship with Genentech.

JAMA Oncol. Published online on August 30, 2018. Abstract

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