PracticeUpdate: Haematology & Oncology

ESMO 2016

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EXPERT OPINION ARLENE SIEFKER-RADTKE Current concepts inmanaging rare histologies in bladder cancer Interview by Sumanta Kumar Pal MD Dr Pal and Arlene Siefker-Radtke, MD, discuss a variety of rare bladder cancer histologies and their management at ESMO 2016.

Dr Pal: I’m here with one of my idols of the GU medical oncology space, Dr Arlene Siefker- Radtke. Something that I always call upon you for is how to manage rare histologies of bladder cancer. I think many of us around the country acknowledge you as being the foremost expert in that area. We were having a little dialogue earlier about an abstract that touches on small- cell carcinoma of the bladder. Can you tell us a little bit more about the data that’s been presented here and some of the caveats? Dr Siefker-Radtke: This was a retrospective trial in small-cell urothelial cancer, so it’s actually retrospective data. I don’t believe patients signed prospective consent. And they are cor- rect, it is one of the largest groups of small-cell patients that were presented, but the popu- lation of patients that were actually treated with neoadjuvant chemotherapy is actually relatively low. There’s been other institutions, like MD Anderson where we’ve published more patients receiving neoadjuvant aggressive chemotherapy. In the small-cell abstract at this meeting, there was a suggestion that there’s no benefit from either neoadjuvant or adjuvant chemotherapy for small-cell tumours of the bladder. Now that’s different from what we’ve previously published, where we found that giving an aggressive chemotherapy regimen, and the majority of our patients, probably over 80%, received a combination of ifosfamide Adriamycin, which we alternated with etoposide cisplatin. And what we saw retrospectively was that giving this aggressive treatment resulted in a statistically significant improvement in survival compared to patients who underwent surgery first, regardless of whether they received adjuvant treatments. In the abstract here at ESMO, when you look at the group of patients who actually received

those tumours may behave in a microcapillary fashion, and if we exclude them from our clini- cal trials, then we might actually miss groups of patients who would benefit from a specific targeted treatment.

exclude those patients from the trial, but as we start understanding more about the biology, I think this is going to have to change, and I would argue we should start including these patients because the biology might actually predict the benefit with specific agents. For instance, when we look at microcapillary tumours, we see enrichment for perhaps HER2 signatures in that group of patients. And even when Bogdan Czerniak and Charles Guo in our group did some subtyping work in microcapillary, where they would isolate the microcapillary component, and then an adjacent urothelial component that did not have microcapillary features and what they found is that by gene expression profiling they essentially overlap. They appear biologically to be the same tumour, so even if there’s a less than 50% component of microcapillary

chemotherapy, it was 24 patients receiving neoadjuvant treatment. I think our group was over 50 patients, and of the neoadjuvant patients, only half of those, so approximately 12, received a cisplatin-based regimen like etoposide cisplatin, the other half received etoposide carboplatin. So, it’s certainly pos- sible that etoposide carboplatin isn’t enough to engender benefit in the neoadjuvant setting for small-cell tumours of the bladder, and perhaps with more patients treated with a more aggres- sive regimen, maybe they would have seen a different result. Dr Pal: I have to say, from my own personal experience, and these are cases that I’ve shared with you, I’ve seen phenomenal responses with this regimen of Adriamycin ifosfamide followed by cisplatin etoposide, really, concur- rent with what you’ve just outlined. Another

Dr Siefker-Radtke is Associate Professor,

Department of Genitourinary Medical Oncology, Division

of Cancer Medicine, The University of Texas MD Anderson Cancer Center, and Clinical Co-Leader of Bladder SPORE Executive Committee in Houston, Texas.

Watch the full interview at PracticeUpdate.com

question for you: again, with all the buzz around immuno-oncol- ogy, the question that frequently comes up in our clinic is whether or not these agents are applicable to patients with rare histologies. So if I see a patient with a mix of transitional cell and small-cell, a mix of transitional cell and adenocarcinoma, is it reasonable to potentially apply I-O in that setting? Dr Siefker-Radtke: Well, the way we’re thinking about bladder can- cer is definitely changing. In the past, all of our trials would exclude patients with a predominant non- urothelial component. So if we saw predominantly small-cell tumours, predominantly adeno- carcinomas, microcapillary, or sarcomatoid, we would typically

Chemoradiation outcomes poorer in elderly patients with newly diagnosed glioblastoma Progression-free and overall survival in patients older than 65 years with newly diagnosed M aría Martínez García, MD, of the Catalan Institute of Oncology, Badalona,

© ESMO 2016

In multivariate analysis, of elderly patients, gross total resection and pseudoprogression but not Karnofsky performance status or O6-methylgua- nine-DNA methyltransferase were independent predictors of overall and progression-free survival. Dr Martínez García concluded that progression-free and overall survival were confirmed to be poorer in patients older than 65 years of age. Pseudoprogression exerted a significant impact on overall survival. None of the elderly patients studied presented the isocitrate dehydroge- nase 1 mutation. For elderly patients, the type of resection and O6-methylguanine- DNAmethyltransferase methylation status were the more relevant prog- nostic factors in patients with newly diagnosed glioblastoma treat- ed according to the Stupp regimen. She added, “Since we have tissue available from all of these patients, we are performing molecular analy- sis, and will have the results of this analysis soon.”

of age and younger (P = 0.006). Isocitrate dehydrogenase 1 status was characterised in 82 patients older than 65 years of age, none of whom presented mutated isocitrate dehydrogenase 1 versus 10 (5.6%) in younger patients (P = 0.029). Median follow-up was 13.5 months. In the global population, median progression-free and overall survival were 8 (95% CI 7.49–8.5) and 14 months (95% CI 12.74– 15.25), respectively, vs 7 (95% CI 6.09–7.9) and 10 months (95% CI 7.97–12.02) in patients age 65 years and younger and those older than 65 years of age (P = 0.020 and < 0.000), respectively. Median overall survival in elderly patients presenting pseudoprogres- sion was 16 (95% CI 13.23–18.76) versus 9 months (95% CI 7.29– 10.7) without pseudoprogression (P = 0.022). Patients with meth- ylated O6-methylguanine-DNA methyltransferase suffered a higher incidence of pseudoprogression (P = 0.05).

whether we could identify useful prognostic factors.” In a study of patients with newly diagnosed glioblastoma treated with chemoradiation according to the Stupp regimen, outcomes and prognostic factors were analysed in patients older than 65 years of age. Dr Martínez García reported the final survival and new data regarding pseudoprogression and molecular analysis. Between 2005 and 2014, 148 patients over 65 years of age were enrolled. A total of 117 (79%) were 65–75 years of age and 31 (21%) were older. Median age was 72 years. Among those older than 65 years of age, 19 (14.7%) presented pseudoprogression versus 42 (17.6%) of younger patients (dif- ference not significant). O6-methylguanine-DNA methyl- transferase methylation status was characterised in 116 patients, of whom 65 (56%) of patients older than 65 years of age were methyl- ated vs 87 (40.3%) of those 65 years

Spain, explained that glioblastoma incidence is growing in elderly patients, and approximately 50% of these patients are over 65 years of age. No standard treatment has been established for newly diagnosed glioblastoma in elderly patients. The elderly population lacks reliable, molecular prognostic factors. “The elderly population with glioblastoma is an important group,” she said, “for whom no standard treatment is available. Dr Perry’s presentation of results of a phase 3 randomised controlled trial of short-course radiotherapy with or without concomitant and adjuvant temozolomide in elderly patients with glioblastoma at ASCO 2016 was highly relevant.” She added, “We wanted to determine the outcomes for elderly patients treated with standard chemoradiation (Stupp regimen) outside of clinical trials, and

glioblastoma have been shown to be poorer, finds a substudy of patients age 65 and older from a larger multicentre study.

VOL. 1 • No. 5 • 2016