Upper tract urothelial carcinoma (UTUC) is a rare malignancy with a mortality rate of over 50% for locally advanced disease. However, few clinical trials have been conducted due to its low incidence rate. Nephroureterectomy—a surgical procedure in which the renal pelvis, kidney, ureter, and bladder cuff are removed—is considered the standard treatment approach for patients with UTUC, but little research had been conducted regarding the optimal treatment after surgery. In the phase 3 POUT trial, a team of researchers led by Alison Birtle, MD, a consulting clinical oncologist at Royal Preston Hospital's Rosemere Cancer Centre in Preston, the United Kingdom, found that adjuvant platinum-based chemotherapy significantly improved outcomes in patients with locally advanced UTUC who had undergone nephroureterectomy. In this interview with i3 Health, Dr. Birtle discusses the significance of the POUT trial—the largest randomized clinical trial to be conducted in this patient population—and the benefits in survival and quality of life that adjuvant platinum-based chemotherapy has to offer for patients with locally advanced UTUC.
What are some of the most challenging aspects of treating patients with locally advanced UTUC after nephroureterectomy?
Alison Birtle, MD: Firstly, one of the greatest challenges in this patient group was that before POUT, there was no particular evidence to guide treatment after nephroureterectomy. There was no evidentiary basis for chemotherapy, and there were no randomized controlled trials, so treatment was done on a case-by-case basis. Secondly, this is a cancer that is not common. Being able to sufficiently recruit enough patients for a trial of this size is extremely challenging because a lot of smaller centers might only see one or two patients with this disease per year.
The third issue is knowing the right time to give chemotherapy. Should you give it before surgery when the patient has two kidneys, or should you give it afterwards when they have only one kidney? There are pros and cons to all of the approaches. We decided to make POUT an adjuvant trial because before we started the study, we did a survey across the whole of the UK of patients in a focus group and also of clinicians. We found that clinicians across the UK were concerned that if they gave chemotherapy before surgery, they wouldn't be 100% certain that the patient had invasive cancer, and they would therefore be overtreating some patients who didn't need chemotherapy. In fact, there had been a couple of studies looking at patients who had been thought to have obvious cancers on their scans before they went ahead with nephroureterectomy, but ultimately they were found to not have cancer at all.
We were really worried that we might overtreat patients who had T1 disease and a good prognosis and who didn't need chemotherapy, as well as patients who didn't have UTUC at all, but rather a different sort of cancer, such as adenocarcinoma or squamous cell carcinoma. We also talked to the patients about it, and when we explained the situation, they were much keener to know that they definitely had invasive cancer before undergoing surgery. That's why we set POUT up as an adjuvant study.
What is the significance of your findings regarding adjuvant chemotherapy for patients with locally advanced UTUC after nephroureterectomy?
Dr. Birtle: This is a huge step forward for patients with UTUC. We call these types of diseases "Cinderella cancers" because we always feel very passionately about our own tumor type that we treat, but genuinely, nobody really cared about UTUC prior to this because it's seen in a relatively small number of patients. These patients do worse stage-by-stage than those with bladder cancer, with whom a number of similarities are shared, but nobody had done any randomized studies in this particular stage of UTUC before.
We did manage to recruit enough patients, and it was a triumph that every single uro-oncologist in the UK got behind this study—the oncologists, the urologists, the specialist nurses, as well as the patients. We had 75 centers open, of which 57 recruited at least one patient. The study enrolled 261 patients, and to have such a massive difference in favor of chemotherapy was fantastic and really showed that we are significantly improving the amount of time before progression and preventing metastasis.
The trial also showed that giving chemotherapy is very achievable. We were able to safely give chemotherapy with cisplatin/gemcitabine, or with carboplatin/gemcitabine if the patient's renal function wasn't good enough for cisplatin. We were able to administer all four cycles to 71% of patients, and there were no unexpected side effects outside of what we normally see with these drugs. For the first time, we also now have quality of life data for these patients. It shows that they do get a temporary dip in their quality of life, which coincides with the usual third or fourth cycle of chemotherapy, but then it recovers to baseline very quickly. There are no long-term side effects in terms of quality of life, and that was very reassuring. This study showed a whopping benefit in favor of chemotherapy.
What further research is needed regarding adjuvant chemotherapy for patients with locally advanced UTUC after nephroureterectomy?
Dr. Birtle: I think that there are lots of other things that we could do. We have the tissue samples for the patients enrolled in the trial, and we'll be analyzing those to look for things that are either upregulated or downregulated to determine whether we could manage to predict which patients are more likely to benefit than others. There are also some newer agents coming out at the moment: immunotherapy drugs and targeted therapy drugs, like those that work against the fibroblast growth factor receptor (FGFR). It will be really interesting to find out if other drugs will provide a benefit in this setting. But obviously, we now have the evidence to say that adjuvant platinum-based chemotherapy should be the standard of care for these patients.
Do you have any words of advice for community oncologists, urologists, and other members of the cancer care team treating patients with locally advanced UTUC?
Dr. Birtle: We now have evidence from a large, pragmatic study done in many sites across the UK showing that we really should consider this treatment for all patients with UTUC whose tumors fulfill the criteria: T2 to T4 tumors that could be node-positive preoperatively as long as any visible nodes were removed at the time of surgery, followed by a negative post-operative computed tomography (CT) scan. Cisplatin/gemcitabine should be considered first, or carboplatin should be substituted for cisplatin if renal function isn't good enough. There are no additional toxicities compared to those that are normally seen with these drugs. Adjuvant chemotherapy should be the standard of care and should be offered to all appropriate patients with locally advanced UTUC.
About Dr. Birtle
Alison Birtle, MD, is a consultant clinical oncologist and an honorary clinical senior lecturer at Royal Preston Hospital's Rosemere Cancer Centre in Preston, UK. She is also a member of the Research and Innovation Committee at Lancashire Teaching Hospitals National Health Service (NHS) Foundation Trust, secretary of the British Uro-Oncology Group, and a medical advisor and Trustee of Fight Bladder Cancer. Dr. Birtle specializes in the treatment of genitourinary malignancies, including prostate, testicular, and bladder cancers. Her research focuses on developments in chemotherapy, targeted therapy, and radiotherapy for patients with urological tumors.
For More Information
Birtle A, Johnson M, Chester J, et al (2020). Adjuvant chemotherapy in upper tract urothelial carcinoma (the POUT trial): a phase 3, open-label, randomised controlled trial. Lancet. [Epub ahead of print] DOI:10.1016/S0140-6736(20)30415-3
Transcript edited for clarity. Any views expressed above are the speaker's own and do not necessarily reflect those of i3 Health.