AT THE GENITOURINARY CANCERS SYMPOSIUM

SAN FRANCISCO (FRONTLINE MEDICAL NEWS) – Patients who have undergone nephro-ureterectomy for upper-tract urothelial cancer (UTUC) fare much better if they are given adjuvant chemotherapy, according to the first results of the POUT trial reported at the 2018 Genitourinary Cancers Symposium.

Standard treatment for this rare cancer is radical nephro-ureterectomy followed by surveillance, noted lead author Alison Jane Birtle, MD, MRCP, FRCR, a consultant clinical oncologist at the Rosemere Cancer Centre, Royal Preston Hospital, Preston, United Kingdom. Evidence has been insufficient to recommend adjuvant therapy.

“We know that UTUC shares a similar etiology with bladder cancer, where there is strong evidence for chemotherapy,” she said. “Trials of adjuvant chemotherapy in bladder cancer have been challenging because of cystectomy being a much more morbid operation. So adjuvant chemotherapy after nephro-ureterectomy should be much easier to give because of the less morbid procedure.”

The POUT (Peri-Operative Chemotherapy Versus sUrveillance in Upper Tract Urothelial Cancer, NCT0199397) investigators enrolled in the trial 261 patients from 57 UK centers who had undergone radical nephro-ureterectomy for urothelial cancer of the renal pelvis or ureter. Patients were randomized evenly to receive surveillance or adjuvant platinum-based combination chemotherapy, with specific platinum (cisplatin or carboplatin) based on glomerular filtration rate (GFR).

Trial enrollment was stopped early, after a median follow-up of 19.3 months, because of efficacy of chemotherapy, Dr. Birtle reported at the symposium, which was sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

Main results showed that risks of both disease-free survival events and metastasis-free survival events were 51% lower for the chemotherapy group as compared with the surveillance group. Overall survival showed a trend toward benefit as well.

Not surprisingly, grade 3 or worse adverse events during treatment were about four times more common with chemotherapy, but the treatment was overall feasible and safe, even though the majority of patients were older than 60 years.

“Based on these results, adjuvant platinum-based chemotherapy should be considered a new standard of care in these patients,” Dr. Birtle maintained. “The next thing is how are we going to move this data forward? We are looking at the successor study at the moment, which is currently in development…[POUT] has been a triumph of UK urologists really getting behind it, but to do a further study, it would be great to look at international collaboration.”

Optimal timing of chemotherapy, before or after surgery, remains an open question, according session co-chair Jeanny B. Aragon-Ching, MD, a medical oncologist with the Inova Medical Group, Fairfax, Virginia.

“This trial offers high-level evidence for consideration of adjuvant chemotherapy in those who are unable to receive neoadjuvant chemotherapy in UTUC, although it is still important to evaluate what the prospective neoadjuvant chemotherapy data in UTUC would show,” she said in an interview. “Ongoing studies include the ECOG 8141 study (clinicaltrials.gov NCT02412670), but certainly, several retrospective trials showed benefit of neoadjuvant chemotherapy in UTUC.”

Other viewpoints

“It’s fantastic that we finally have data in upper-tract cancer. However, I worry about how this data is going to be interpreted, and I argue that it should not be considered the standard of care,” session attendee Matthew Campbell, MD , of the MD Anderson Cancer Center, Houston, commented during a question and answer period.

“I believe that this is showing that chemotherapy is very important in this disease, and if anything, it should be moved into the neoadjuvant setting, where more patients will be cisplatin candidates. Though there is challenge with staging upper-tract disease, at MD Anderson, we consider patients with high-grade disease or hydronephrosis to be at high enough risk to consider for neoadjuvant chemotherapy, and that’s been our approach.”

“When we looked at developing POUT, there was a big debate about whether it should be a neoadjuvant or adjuvant study,” Dr. Birtle replied. UK oncologists expressed concern that not all patients have histologic confirmation of UTUC preoperatively; therefore, chemotherapy could lead to overtreatment for some.

“We plan to go back and look at the CT urograms and the diagnostic imaging done prior to surgery just to see if we can be 100% confident in our diagnostic accuracy preoperatively, to see if we would be more confident with a neoadjuvant study,” she added. The investigators have also reviewed data from the British Association of Urological Surgeons on the postoperative dip in GFR. “It didn’t really seem from that 2015 data that there was a huge unmet need for patients postoperatively, where we would have missed them had we not treated them preoperatively,” she said.

On a related note, session attendee Surena Matin, MD , also of MD Anderson, asked “How many patients were potentially precluded because of their GFR, and do you have any data regarding response rates in the carboplatin arm?”

The main reason for exclusion was ineligible pathology and not GFR, according to Dr. Birtle. “This goes back to the previous question of can you be certain that a patient has locally advanced disease prior to nephro-ureterectomy? About 60% of patients who were thought to have muscle-invasive disease ultimately on nephro-ureterectomy didn’t.”

Confidence intervals for chemotherapy benefit in the subgroup given carboplatin were wide and overlapped unity, but still favoring benefit and falling within the overall treatment effect, she said.

Session attendee Joaquim Bellmunt, MD , Dana-Farber Cancer Institute, Boston, noted that the chemotherapy benefit was not significant in that subgroup and also in the subgroups with lymph node–positive disease and with positive margins. “I think that saying … chemotherapy is for everybody based on this trial” is incorrect, he asserted. “It may be good just to tone down the message that this is the new standard of care.” He further questioned the trial’s early stopping, noting that continuing would have provided more information in these patients.

Those subgroups were small, so analyses were underpowered to definitively rule out chemotherapy benefit, according to Dr. Birtle. The investigators had intensive discussion about the recommendation to stop early, because of a goal to determine overall survival impact. Ultimately, “when we saw the data in terms of disease-free survival and metastasis-free survival, the magnitude of the effect was so big that we felt it was uncomfortable and unethical not to offer patients treatment,” she said.

Study details

Patients in POUT’s chemotherapy arm received four cycles of chemotherapy—gemcitabine-cisplatin if their GFR was 50 mL/min or higher, or gemcitabine-carboplatin if their GFR was 30-49 mL/min—starting within 90 days of nephro-ureterectomy.

Of note, approximately 40% of all patients in the trial were aged 70 years or older, including the 5% who were aged 80 years or older. “This is very reassuring for a study of adjuvant platinum-based chemotherapy,” Dr. Birtle commented. Fully 71.2% of the chemotherapy patients received all four planned cycles.

In an intention-to-treat analysis, risk of disease-free survival events (death from any cause, metastasis, or any ureteric or renal bed recurrence) was sharply reduced with chemotherapy versus surveillance (hazard ratio, 0.49; P=.001). The proportion of patients event free at 2 years was 71% in the chemotherapy group and 54% in the surveillance group. Benefit was generally similar across subgroups, and findings were much the same after adjustment for nodal involvement, microscopic margin status, and planned chemotherapy regimen (hazard ratio, 0.47; P=.001).

Risk of metastasis-free survival events was also sharply lower with chemotherapy (hazard ratio, 0.49; P=.002), with a proportion event free at 2 years of 74% in the chemotherapy group and 60% in the surveillance group. These findings were also much the same after adjustment for the above factors (hazard ratio, 0.47; P=.002).

Overall survival tended to be better with chemotherapy than with surveillance (hazard ratio, 0.55), but data are still immature for this endpoint.

The rate of grade 3 or worse adverse events during the treatment period was 53.2% with chemotherapy and 13.5% with surveillance; events with chemotherapy were as expected, with neutropenia, thrombocytopenia, and gastrointestinal events predominating. The rate of febrile neutropenia was 5.7% with gemcitabine-cisplatin and 7.8% with gemcitabine-carboplatin, but there were no neutropenic deaths.

The rate of grade 3 or worse adverse events for the entire trial period was 62.1% with chemotherapy and 24.8% with surveillance.

Data on nephrotoxicity are still being evaluated, according to Dr. Birtle. Only seven patients who started on gemcitabine-cisplatin had to switch to gemcitabine-carboplatin because their GFR fell.

In a related translational study, the investigators are evaluating both the baseline CT urograms and the resected tumors to identify prognostic and predictive markers, she said.

Dr. Birtle disclosed that she receives honoraria from Roche, Janssen, Astellas, and Bayer, and is a consultant to Sanofi-Aventis. The trial was funded by the UK Clinical Trials Awards and Advisory Committee.

SOURCE: Birtle A et al. Genitourinary Cancers Symposium. Abstract 407

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