'Cinderella' Cancer Gets Trial With Fairy-tale Ending

Nick Mulcahy

February 12, 2018

SAN FRANCISCO — "Congratulations for doing the undoable," said Surena Matin, MD, a urologic oncologist at the University of Texas MD Anderson Cancer Center, Houston, standing at a microphone station on the meeting floor here at Genitourinary Cancers Symposium (GUCS) 2018.

Matin was addressing Alison Birtle, MD, a consultant clinical oncologist at the Rosemere Cancer Center, Royal Preston Hospital, Fulwood, United Kingdom, who was at the speakers' podium in front of the gathering.

She had just finished reporting on the design and conduct of a phase 3 randomized clinical trial in upper tract bladder cancer, a "rare" malignancy in which only about 1400 new cases occur per year in the United Kingdom.

Birtle and her UK colleagues not only managed to successfully perform a trial in upper tract bladder cancer in 261 patients, they also claimed to have established "a new standard of care."

The trial, known as POUT, demonstrated for the first time that chemotherapy after surgery improved disease-free survival (DFS) in upper tract urothelial cancer, compared to observation after surgery. Most of the study patients had locally advanced disease.

The 2-year DFS was 71% for the chemotherapy group vs 54% for the surveillance group (HR = 0.49; P = .001).

POUT is the best-run trial to date in these patients, agreed Sumanta Pal, MD, urologic oncologist at City of Hope Cancer Center in Duarte, California, who was asked for comment. "Every other trial we had in this space has suffered from methodological issues, such as poor accrual or attrition due to not sticking to the treatment algorithms," he said.

"I think this is going to change management," said Pal.

I think this is going to change management. Dr Sumanta Pal

Meeting attendees apparently agreed. In a #GU18 Twitter poll, 62% of 73 respondents cited POUT as the "main practice change" presented at the meeting (the SPARTAN trial was a distant second, at 19%).

After her presentation, Birtle told reporters that upper tract urothelial cancer is "a very neglected tumor" for which there is "no real interest" from researchers worldwide, owing to its low incidence.

"It's a real genuine Cinderella cancer," she said, explaining that, in the universe of genitourinary cancer research, prostate and lower tract bladder cancer dominate. Upper tract bladder cancer, or upper tract urothelial cancer, consists of malignancy in the ureter, kidney, and related tissue.

Birtle knows a bit about hardworking underdogs. Earlier in her career, she was at the famed research-intensive Royal Marsden Hospital in London before relocating to take care of her parents. She joined the relatively less glamorous Royal Preston Hospital in Preston, where she is a full-time clinician. Birtle, who is an award-winning investigator, served as lead investigator for POUT, "with no time allowance in my clinical schedule." In short, she ran the trial in her spare time.

The trial, which is the largest randomized trial ever conducted in these patients, was stopped early because of outstanding efficacy of chemotherapy, which was mostly gemcitabine-cisplatin. For patients whose kidney function score was low, gemcitabine-carboplatin was used.

"Based on these results, adjuvant platinum-based chemotherapy should be considered a new standard of care in these patients," Birtle told the GUCS audience.

Not everyone in the audience agreed.

For example, Matthew Campbell, MD, urologic oncologist from MD Anderson, flatly disagreed, saying adjuvant therapy "should not be standard of care." If these patients are to be treated with chemotherapy, it should be administered before surgery or as neoadjuvant therapy, which is the preferred choice at MD Anderson, he said.

Academics from Dana Farber Cancer Institute in Boston and the University of Chicago also challenged Birtle with objections, and they too touted neoadjuvant use.

In a conversation with Medscape Medical News, Birtle said the main objection from the neoadjuvant chemotherapy camp concerned safety.

She explained that for upper tract urothelial cancer, nephro-ureterectomy is performed. That procedure involves removing one kidney, ureter, and other tissue. If chemotherapy is given before surgery, the patient still has two kidneys with which to process the toxicity associated with chemotherapy, which is obviously preferable to one.

But there are competing safety concerns, in light of which chemotherapy after surgery is advantageous — a factor that tips the scales toward adjuvant use, Birtle emphasized.

She explained that approximately 10% of suspected upper tract urothelial cancers will prove not to be cancerous upon excision and subsequent examination. "There is a lack of definitive histological diagnosis in some patients," she said. She explained that it is not possible to perform a biopsy in some upper tract bladder cancers, owing to the thinness of the tissue wall.

In addition, 10% to 15% of cases are found at surgery not to be invasive of muscle and therefore are "superficial" tumors. In such cases, chemotherapy is not needed, Birtle explained. "There is a concern about overtreatment," she summarized.

The main reason for patients not being able to enroll in the POUT study was "ineligible pathology," said Birtle. This raises the question of whether or not you can tell that a patient has locally advanced disease prior to nephro-ureterectomy, she said. Approximately 60% of patients who were thought to have muscle-invasive disease were found not to have such disease after surgery. "That was the biggest exclusion" in the trial, she said.

Currently, there is no international consensus on systemic therapy for these patients because of a "paucity" of data, said Birtle.

Katrin Schlack, MD, a urologist at the University Hospital of Meunster, attended GUCS and said that "everyone talked about" the POUT study. She offered a German perspective on the controversy.

We usually give chemotherapy after surgery. Dr Katrin Schlack

"We usually give chemotherapy after surgery," Schlack told Medscape Medical News. European guidelines state that neoadjuvant chemo can be offered to these patients, but "it is not required," she said. The guidance also recommends use of adjuvant chemotherapy.

The bigger question is whether or not to give chemotherapy to patients with upper tract endothelial cancers, she said. The patient's tumor stage, kidney function, ECOG performance status, and other factors are considered.

Schlack echoed Birtle's comment about not knowing histology in some upper tract bladder cancers because of the difficulty of conducting a biopsy on tissue there. "Diagnostics in the upper tract are not as good as the lower tract," she said. Evaluating surgically removed tissue can be very helpful in assessing the need for adjuvant chemotherapy, she added.

Birtle had some final thoughts about the neoadjuvant vs adjuvant argument. With POUT, she said, there is finally a well-executed phase 3 trial in the adjuvant setting, she said.

The various champions of neoadjuvant chemotherapy have been advocating it for years — but they still don't have phase 3 clinical trial data in hand, Birtle observed.

But that's understandable, she suggested: It's hard to conduct a clinical trial in a cancer with so few patients.

Extraordinary teamwork produced POUT, she said. "It is a triumph of everybody [in the UK urology community] getting behind the trial in a low-incidence tumor." Of 71 eligible centers in the United Kingdom, 57 enrolled patients in the trial, she observed.

"This is a study that should never have really been done," she added, "because it wasn't with sexy new drugs. It was standard chemotherapy." POUT also had strong input from patients regarding its design, which was extremely helpful but time intensive, she explained.


More Study Details

In POUT, patients were randomly assigned in a 1:1 ratio within 90 days after undergoing surgery either to receive four cycles of chemotherapy or to undergo surveillance. Patients underwent cross-sectional imaging and cystoscopy at 6-month intervals for the first 2 years, then annually for 5 years.

Chemotherapy consisted of gemcitabine-cisplatin or gemcitabine-carboplatin if the glomerular filtration rate (GFR) was "poor" (30-49 mL/min).

Patients were excluded if their GFR was especially low (<30 mL/min) or if they had distant metastases, significant comorbidities, or other factors.

The primary endpoint was DSF.

The study was "ambitiously powered" to detect 15% improvement in 3-year DFS. In the surveillance control arm, the 3-year DFS was assumed to be 40%. DFS was defined as time from randomization to death (any cause), metastases, or ureteric or renal bed recurrence.

The independent data and monitoring committee (IDMC) recommended early closure of the trial in November 2017, because the stopping rule had been met.

In the trial, between May 2012 and September 2017, 260 patients were recruited and enrolled. (The planned sample size of the study was 338 patients.) In October 2017, the IDMC recommended that POUT be closed to recruitment, because by that point, the data that had been collected met the early stopping rule for efficacy. At the time of interim analysis, median follow-up was 17.6 months.

The median age of the patients was 69 years. Baseline characteristics included pathologic stage. Most cases were stage pT2 (23.3%) or pT3 (68.2%); the latter is locally advanced disease.

Compliance was "very good," the researchers reported. In terms of adverse events, the trialists saw "the standard side effects you see with chemo," said Birtle. Specifically, 53.2% of the chemotherapy group experienced toxicities of grade 3 or higher, vs 13.5% of the surveillance group.

For the secondary endpoint of metastasis-free survival (MFS), the 2-year rate was 60% for surveillance and 74% for chemotherapy. MFS favored chemotherapy (HR = 0.49; P = .002).

There was also early indication that chemotherapy improved overall survival, said Birtle, but the data need maturation.

Having already accomplished much, Birtle said she would like to obtain international research partners and perform a larger confirmatory trial. She also said that future research should combine chemotherapy with immunotherapies.

The study was funded by Cancer Research UK and sponsored by the Institute of Cancer Research. Dr Birtle has financial ties with Janssen, Roche, Astellas Medivation, AstraZeneca, Bayer, and Sanofi. Other investigators also have ties to industry.

Gastrointestinal Cancers Symposium (GICS) 2018. Abstract 407. Presented February 9, 2018.

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