Conference Coverage: ASCO Genitourinary Cancers Symposium

Evidence-Based Oncology, April 2018, Volume 24, Issue 5

Coverage from the American Society of Clinical Oncology Genitourinary Cancers Symposium, held February 8-10, 2018, in San Francisco, California

Medicaid Expansion Led to Earlier Stage at Diagnosis of Testicular Cancer

Jaime Rosenberg

When Medicaid expansion began in 2014, under the Affordable Care Act (ACA), there started to be fewer uninsured patients and a shift to earlier-stage cancer at the time of diagnosis for patients with testicular cancer in states that adopted the expansion, according to findings presented February 9, 2018, at the American Society of Clinical Oncology Genitourinary Cancers Symposium, which was held in San Francisco, California.

“We all know insurance status is a key determinant of cancer outcomes,” said Xinglei Shen, MD, radiation oncologist, University of Kansas Medical Center. “People who don’t have insurance do poorly, and the ACA sought to improve outcomes by improving access to insurance.”

Shen and his co-author hypothesized that Medicaid expansion would lead to earlier diagnoses and more guideline-concordant treatment for patients with testicular cancer. They looked at the Surveillance, Epidemiology, and End Results (SEER) data from 2010 to 2014, which provides information on cancer statistics, and identified 12,731 cases of testicular cancer during the time period. The time frame of 2010 to 2013 was used as the pre-expansion group.

The expansion states included in the analysis were California, Connecticut, Hawaii, Iowa, Kentucky, Michigan, New Jersey, New Mexico, and Washington. Nonexpansion states included Arkansas, Georgia, Louisiana, and Utah.

Looking at Medicaid enrollment numbers for the SEER states that did not expand coverage, there was a modest increase in the amount of people on Medicaid versus a robust increase in those enrolled in expansion states, said Shen. The biggest change was seen in New Mexico, which had a 50.3% increase.

For insurance status at time of diagnosis, Shen et al found that in expansion states, there was a significant drop in patients who were uninsured at the time of diagnosis: from 8.7% to 4.3%, and a corresponding increase in the proportion of people enrolled in Medicaid: from 14.8% to 19.4%.

In nonexpansion states, there were no significant changes, according to Shen.

There was also an effect on the stage at diagnosis. In states that expanded Medicaid, 20.2% of patients had stage III cancer at the time of diagnosis, down from 27.1% before expansion. There was also a corresponding increase in the proportion of patients diagnosed at stage I, according to Shen. For states that did not expand coverage, 29.2% of patients had stage III cancer at the time of diagnosis, up from 23.2% before 2014.

Lastly, they look to see if there was an effect on quality of care, but the results did not indicate a significant difference. Shen concluded by indicating that longer-term follow-up is needed to study how Medicaid expansion would affect cancer outcomes and survival.

Reference

Shen X, TenNapel M. Impact of Medicaid expansion on diagnosis and management of patients with testicular cancer. J Clin Oncol. 2018;36(suppl 6S; abstr 551) meetinglibrary.asco.org/record/157230/abstract.

Combining Radiation and Immunotherapy in Patients With Bladder Cancer

Jaime Rosenberg

"I think this is an exciting time in the treatment of bladder cancer and really oncology in general, because we’re learning to harness the body’s immune system against malignancies,” said Abhishek Solanki, MD, MS, assistant professor, Radiation Oncology, Loyola University of Chicago, during a February 9, 2018, session at the American Society of Clinical Oncology Genitourinary Cancers Symposium. The meeting took place in San Francisco, California.

While discussing the role of immunotherapy in patients undergoing radiation therapy for bladder cancer, Solanki emphasized that it’s also an exciting time because there’s a lot of preclinical data that have led to us evaluating this approach. Radiation is a local therapy, delivered for local purposes, like treating a primary tumor and in a bladder preservation case, he said. It’s also known that immune invasion is a critical hallmark of cancer and the main mechanisms by which tumors grow, progress, and metastasize.

According to Solanki, there’s emerging evidence that suggests that one of the reasons radiation is effective is because it is immune driven. Cytotoxicity related to radiation releases tumor antigens, which leads to activation of antigen-presenting cells and migration to the lymph nodes and, in turn, priming of T cells. There’s also a release of cytokines that lead to T-cell trafficking back to the tumor and an increased expression of major histocompatibility complex, class I, known as MHC1, within tumor cells. All of these things together lead to cell-mediated death, said Solanki.

However, radiation itself rarely leads to long-term immune memory and the ability to prevent late recurrences. Additionally, there’s emerging data that suggest that radiation can lead to upregulation of programmed cell death-1/programmed death ligand-1 (PD-L1) and regulatory T-cell infiltration into the tumor cell, suggesting that there may be some immunosuppressant effect of radiation.

“This brings us to the hypothesis that we can combine radiation immu- notherapy to improve local control through radiosensitization by bypassing those resistance mechanisms,” said Solanki. “Potentially, by combining these modalities, we can improve systemic response and have long-lasting immune memory when we combine these agents.”

Solanki cited what he said is one of the only studies of bladder cancer specifically looking at the question of the combination of radiation immunotherapy. Investigators implanted bladder cancer tumors in mice and then separated them into 2 groups: one treated with radiation alone and the other treated with radiation and an anti—PD-L1 antibody. With radiation, there was a decrease in the size of the tumor, but it started growing again shortly after. In the combination group, there was more durable and more significant tumor control.

“This leaves us with 2 clinical questions,” said Solanki. “The first is with our traditional paradigms of bladder preservation and definitive chemoradiation therapy. Can we use immunotherapy to improve the outcomes? On the flipside, for patients who have metastatic disease who are being treated with checkpoint inhibitors and for palliation, can we use local radiation to augment that effect and give them more mileage with the available therapies?” Although there is not a lot of data available for bladder cancer, Soalnki said that we can turn to some non—small cell lung cancer (NSCLC) studies that can provide leads on benefits observed.

In the PACIFIC trial, patients with stage III NSCLC receiving definitive chemoradiation with cisplatinum-based chemotherapy were randomized to be administered either placebo or up to 12 months of durvalumab. Investigators found a clear difference in progression-free survival (PFS) that favored the durvalumab group. Also, in the metastatic setting, in the KEYNOTE-001 study, UCLA investigators assessed their NSCLC cohort and found that radiation prior to pembrolizumab was associated with PFS and overall survival.

“Bringing things back to bladder cancer, one of the reasons why it’s hypothesized that immunotherapy’s so successful in NSCLC is because of the high somatic tumor mutation burden, and bladder cancer is right up there,” said Solanki. “And we already have a track record of success with immunotherapy in bladder cancer with [Bacillus Calmette-Guerin] for nonmuscle invasive disease and checkpoint inhibitors for metastatic disease. So I’d argue that bladder cancer is the ideal setting [in which] to investigate the combination of radiation immunotherapy.”

Solanki explained that while there is a lot of clinical and preclinical rationale to combining immunotherapy and radiation for bladder cancer, there’s a lot we don’t know, and the unknown at this time is bigger than the known.

He concluded: “I think it’s up to us, as a community, to find out exactly how best to combine radiation with immunotherapy to augment the effects of both modalities.”

Docetaxel Plus Hormone Therapy Improved Quality of Life, Cost-Effectiveness in Prostate Cancer

Jaime Rosenberg

The addition of docetaxel to first-line long-term hormone therapy in patients with prostate cancer is associated with improved quality of life (QoL) and cost-effectiveness, according to study results presented February 8, 2018, at the American Society of Clinical Oncology Genitourinary Cancers Symposium in San Francisco, California.

Nicholas James, MBBS, PhD, Queen Elizabeth Hospital, presented results from the STAMPEDE trial, which looked at patients with M0 and M1 disease. The primary outcome of the trial was overall survival, and secondary endpoints included failure-free survival (FFS), progres- sion-free survival (PFS), metastatic PFS, skeletal-related events (SREs), toxicity, cost-effectiveness, and QoL.

“Docetaxel produced a very consistent improvement in FFS across the whole trial,” said James. “The other thing that was very consistent across the whole trial was a 40% reduction in symptomatic skeletal events.”

The researchers used a standard model-based approach, explained James. All patients started hormone sensitive and progressed to M0 castration-resistant prostate cancer(CRPC) or M1 lymph node disease, CRPC with bone metastases, CRPC with bone metastases with a SRE, or CRPC visceral. The STAMPEDE trial data were used to determine how much time each patient spent in each cate- gory and what were the QoL implications. The researchers also assessed cost-effectiveness.

Because patients with M0 disease have a 40% delay in the time to relapse, the patients getting docetaxel up front spend more time hormone sensitive than patients in the control arm, said James. Thus, the onset of CRPC M0 or M1 lymph-node only disease is delayed, and patients live fewer months with these conditions or with bone metastases, with or without an SRE. This correlates to a longer period of relatively good QoL and less time with poor QoL. For the metastatic setting, the same effects were observed. Patients spend more time in the hormone-sensitive state, which means less time with the factors that harm your QoL and increase your costs, said James.

“For metastatic patients where there’s a survival advantage, not surprisingly you see a quality-adjusted life years [QALYs] gain as well,” said James. “In other words, the benefits of not relapsing, not having SREs, wipes out the quality-of-life penalty that you incur from your up-front chemotherapy.”

The same effect was seen in patients with M0 disease. Although there wasn’t a robust survival advantage in this setting, there is still a QALY gain.

Over the course of the trial, treatment with docetaxel didn’t change end-of-life costs substantially. But docetaxel costs increased, management costs generally went up, and the costs of other life prolonging therapies went up. However, there’s been big changes over the duration of the trial with the emergence of androgen receptor—targeted therapies, said James.

The researchers remodeled the data using patients who had enrolled later in the trial and who were getting abiraterone/enzalutamide for M1 CRPC. When they did that, there were still increases in docetaxel and management costs and little effect on end-of-life care. However, there was a significant reduction in the use of other life-prolonging therapies compared with the control arm. When looking at net total costs, there was a reduction in overall lifetime care costs in M0 disease from the up-front addition of docetaxel. And although there was a net increase for the metastatic setting, the total cost was approximately £3000 over the lifetime of the patient.

“Up-front docetaxel results in robust gain in quality-adjusted life years in all subgroups,” concluded James. “It supports existing healthcare policy in metastatic patients, but it also supports the use of docetaxel in high-risk nonmetastatic patients.”

Reference

Use of Biomarkers to Identify Patients, Therapies for Neoadjuvant Chemotherapy

James N, Woods B, Sideris E, et al. Addition of docetaxel to first-line long-term hormone therapy in prostate cancer (STAMPEDE): Long-term survival, quality-adjusted survival, and cost-effectiveness analysis. J Clin Oncol. 2018;36(suppl 6S; abstr 162). meetinglibrary.asco.org/record/157020/abstract. Jaime Rosenberg

During the 2018 American Society of Clinical Oncology Genitourinary Cancers Symposium, Peter Black, MD, professor, Department of Urologic Sciences, University of British Columbia, discussed 3 clinical biomarkers that have potential use to select patients and therapies for neoadjuvant chemotherapy (NAC).

Black began the discussion by explaining that there are multiple prospective randomized trials and meta-analyses that demonstrate a survival advantage from NAC. The 2 main limitations with NAC are: Only about 40% of patients seem to be benefiting from the treatment, with the other 60% are potentially suffering from adverse effects from chemotherapy and unnecessary delay in definitive radical cystectomy, and NAC has not been widely adopted in North America or in Europe.

“I think one of the ways forward, to overcome both of these limitations, is with biomarkers,” said Black. “If we have a biomarker that would tell us which patients are likely to respond or not to respond, we can avoid using NAC in the likely nonresponders, and if we had better patient selection, we’d also probably have better buy in for adoption of NAC. “Black identified 3 clinical biomarkers that are in development and close to potential clinical implementation.

Molecular Subtypes

Several research groups have identified a molecular taxonomy for bladder cancer based on RNA expression. The key classifications are basal and luminal cell lines; with basal tumors having a gene expression profile that resembles the basal layer of the urothelium; it’s more stem-like and less differentiated. The luminal tumors, on the other hand, have a gene expression profile that resembles more differentiated luminal cells, Black explained.

According to Black, these subtyping systems have a limitation in that a patient cohort is needed to create a cluster so that an individual patient can be classified in one of the subtypes, which is not practical in clinical practice. So, Black’s team developed a single-patient classifier called a genomic sequencing classifier, or GSC.

It includes 4 cohorts: luminal, luminal-infiltrated, basal, and claudin-low. They next gathered a multicentric cohort of 305 patients, all of whom were receiving NAC, which included 269 patients who received cisplatin-based chemotherapy who were used for all survival analyses. The control population of almost 500 patients who did not receive NAC was based on publicly available data and literature.

“The bottom line with this classifier was, and if you look at the non-NAC patient population, you can see that the luminal patients clearly do better than everyone else,” said Black. “The other 3 cohorts are relatively closer together. In the NAC data set, you can see they jump up the most; they get the most benefit from NAC with respect to survival.”

Coxen Model

A research team at the University of Virginia developed the Coxen model, which is currently being evaluated in a clinical trial. The model was initially based on the National Cancer Institute 60 cell line (NCI-60) panel of cancer cell lines, none of which were bladder cancer; however, it’s a comprehensive database of gene expression and IC50 values for over 100,000 compounds, said Black. The team was able to integrate bladder cancer data, gene expression data and a panel of bladder cancer cell lines, and through bioinformatics techniques, was able to come up with a predictive model for any given drug based on gene expression.

Genomic Alterations, Mutations, and Copy Number Changes

A research team led by Eliezer Van Allen, MD, from Dana-Farber Cancer Institute, and Jonathan Rosenberg, MD, from Memorial Sloan Kettering Cancer Center, examined EERC2 mutations in a cohort of 50 patients. The team compared 25 patients who received cisplatin-based chemotherapy and had a complete response with 25 who had residual muscle-invasive disease. According to Black, the ERCC2 gene was predominant in the responders, while nonre- sponders did not carry ERCC2 mutations.

Combining Subtypes and Mutations

Black concluded by demonstrating what would happen if the subtyping and mutation biomarkers were put together. “One-third of patients are basal, and if you add in the patients who have the DNA repair gene mutations, you end up with about 50% of patients who we would predict would respond well to cisplatin-based chemotherapy based on a combination of mutations and subtyping,” said Black.