University of Michigan Rogel Cancer Center

External beam radiotherapy (EBRT) plus androgen deprivation therapy (ADT) showed superior overall survival (OS) compared with EBRT plus a brachytherapy boost (BT) in men with intermediate- and high-risk prostate cancer, according to findings from a network meta-analysis that were published in the 

Study investigators pooled data from 9 randomized trials. Six trials compared EBRT with or without ADT (n = 4663), and 3 studies compared EBRT with or without BT (n = 718) in this patient population. Results showed that the addition of ADT to EBRT improved OS (HR, 0.71; 95% CI, 0.62-0.81), whereas adding BT to EBRT did not lead to a significant improvement in OS (HR, 1.03; 95% CI, 0.78-1.36). In the network meta-analysis, EBRT plus ADT showed a significant improvement in OS versus EBRT plus BT (HR, 0.68; 95% CI, 0.52-0.89). Additionally, Bayesian modeling demonstrated an 88% probability that EBRT plus ADT resulted in superior OS compared with EBRT plus BT.

“In our analysis of men with intermediate- or high-risk prostate cancer, the addition of ADT to EBRT seems to improve survival, whereas the addition of a brachytherapy boost did not, and this remained true on meta-analysis,” lead study author William C. Jackson, MD, of University of Michigan, and co-investigators wrote. “Our findings demonstrate that there is a high probability that EBRT plus ADT provides superior OS compared with EBRT plus a brachytherapy boost in men with intermediate- and high-risk prostate cancer. Our study suggests that ADT should not be omitted on the basis of available evidence in men with intermediate- or high-risk prostate cancer receiving EBRT plus a brachytherapy boost.”

Each trial had published data on biochemical recurrence-free survival (bRFS) and OS between January 1980 and June 2018.

The data that were compiled included the years the trial accrued, median follow-up, patient age, National Comprehensive Cancer Network (NCCN) risk group, clinical T stage, pretreatment prostate-specific antigen (PSA), Gleason score, duration of ADT if administered, and HRs with 95% confidence intervals for bRFS and OS.

The median follow-up of the trials that assessed EBRT with or without ADT was 114 months versus 110.3 months in those that assessed EBRT with or without BT.

Patients had a median age of 70.1 and 67.8 years, respectively.

In the trials that assessed EBRT with or without ADT, 15% of patients had low-risk disease, 42% had intermediate-risk disease, and 41% had high-risk disease. In the trials that assessed EBRT with or without BT, 1% of patients had low-risk disease, 34% had intermediate-risk disease, and 63% had high-risk disease.

The majority of patients (78%) in the EBRT/ADT trials had clinical T1 to T2 prostate cancer and 22% had T3 prostate cancer. Similarly, 70% of patients in the EBRT/BT trials had T1 to T2 prostate cancer, and 30% had T3 disease.

Gleason scores varied between arms. In the EBRT/ADT trials, 50% of patients had a Gleason score of 6, 34% had a score of 7, and 14% had scores between 8 and 10. In the EBRT/BT trials, Gleason scores were 19%, 47%, and 29%, respectively.

The median pretreatment PSA level was 14.6 ng/mL in the patients who received EBRT with or without ADT versus 16.0 ng/mL in those who received EBRT with or without BT.

In the meta-analysis, the Cochran’s Q test for heterogeneity revealed that EBRT plus ADT was not significant versus EBRT alone, after adjusting for ADT duration. Additionally, EBRT plus BT was not significant versus EBRT alone prior to adjusting for ADT duration (Cochran’s Q = 2.61; 

Using the calculated HR of 0.68, the 10-year cumulative incidence of overall mortality was 28% for EBRT plus ADT compared with 41% for EBRT plus BT.

“Given the estimated magnitude of the OS benefit of EBRT plus ADT compared with EBRT plus a brachytherapy boost, we estimated the number of men that would be required to be randomly assigned between these 2 treatments to have 80% power to detect an OS benefit of this magnitude in an attempt to inform future clinical trial design,” Jackson and co-investigators wrote. “Assuming an α of 0.05, an estimated 832 men would need to be randomly assigned to have 80% power to demonstrate a statistically significant difference in OS between these two treatment modalities, assuming a 20% event rate.”

Bayesian modeling further revealed that EBRT alone resulted in a 27% probability of superior OS compared with 30% and 90% for EBRT plus BT and EBRT plus ADT, respectively. These data, which were determined using surface under the cumulative ranking curve, demonstrated that ERBT plus ADT had an 87% probability of leading to superior OS compared with EBRT alone and EBRT plus BT.

“Our findings suggest that the addition of ADT provides a greater oncologic benefit than a brachytherapy boost,” Jackson and co-investigators wrote. “Thus, if a brachytherapy boost is to be used for intermediate- or high-risk disease, our data suggest that the addition of ADT is required to prevent inferior survival compared with EBRT with ADT alone. On the basis of our findings, there is currently insufficient evidence to support the omission of ADT in men with intermediate- or high-risk prostate cancer treated with any form of definitive radiation therapy, including brachytherapy.”

Notably, these findings contrast other retrospective and observational studies which suggest that adding ADT to EBRT does not result in a survival benefit for patients. Instead, the literature suggests that omitting ADT and giving concurrent EBRT plus BT can spare patients ADT or shorten the duration of ADT.

“Our data question the validity of this practice and suggest that the use of EBRT plus ADT provides a high probability of superior OS in comparison with EBRT plus a brachytherapy boost without ADT,” Jackson and co-investigators wrote.

Limitations of this meta-analysis include limited sample sizes from the randomized trials, the inability to control for the radiation dose patients received, the inability to compare the treatment-related toxicity between EBRT plus ADT and EBRT plus BT, and the inability to assess the impact of ADT or BT on distant metastases.

“Randomized trials are needed if the omission of ADT is to be recommended with EBRT and a brachytherapy boost. Future trials comparing ADT and brachytherapy boost should include patient-reported quality of life as a secondary outcome,” concluded Jackson and co-investigators.

Jackson WC, Hartman HE, Dess RT, et al. Addition of androgen-deprivation therapy or brachytherapy boost to external beam radiotherapy for localized prostate cancer: a network meta-analysis of randomized trials [published online ahead of print May 12, 2020]. 

Articles

External beam radiotherapy plus androgen deprivation therapy showed superior overall survival compared with EBRT plus a brachytherapy boost in men with intermediate- and high-risk prostate cancer.

Meta-Analysis Finds Adding ADT to EBRT Extends Survival in Localized Prostate Cancer

The approval of several TKIs and combination regimens has led to more treatment options for patients with renal cell carcinoma (RCC), with a heavier focus on individualized approaches, explained Ajjai Shivaram Alva, MBBS.

“For kidney cancer, we have to treat the patient on an individual basis with regards to the context of the prognostic score by the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC), the histology, and the individual patient's performance status,” said Alva. “Other factors, such as cost and convenience, also play into this. It really has to be a personalized decision, which makes it a little more complicated for the general oncologist. However, thanks to trials and tools like the ASCO guidelines, these can be streamlined.”

Results of the CABOSUN trial demonstrated superiority with frontline cabozantinib (Cabometyx) over sunitinib (Sutent) in patients with advanced RCC, with a median progression-free survival (PFS) of 8.2 months versus 5.6 months, respectively, leading to a 52% reduction in the risk of progression or death (HR, 0.48; 95% CI, 0.31-0.74; 

 Data from an updated analysis showed that, in intermediate- and poor-risk patients, the median overall survival (OS) was 26.6 months (95% CI, 14.6—not estimable) with cabozantinib and 21.2 months (95% CI, 16.3-27.4) with sunitinib, leading to a 20% reduction in the risk of death (HR, 0.80; 95% CI, 0.53-1.21).

Beyond single-agent TKIs, the use of combinations is rapidly growing in RCC with the FDA approvals of 

nivolumab (Opdivo) plus ipilimumab (Yervoy)

pembrolizumab (Keytruda) plus axitinib (Inlyta)

 in the first-line setting for patients with advanced RCC. The nivolumab/ipilimumab approval is specific to intermediate- and poor-risk patients.

 State of the Science Summit™ on Genitourinary Cancers, Alva, an associate professor at the University of Michigan, discusses ongoing advances in the treatment paradigm for patients with metastatic RCC.

: Could you provide an overview of the CABOSUN trial?

: The CABOSUN trial is a randomized phase II trial comparing, in the frontline setting, the multikinase inhibitor cabozantinib with the old standard of care, sunitinib, in patients with RCC. Patients with no prior systemic therapy were enrolled on this trial. The conclusion of this study, which was specifically for intermediate- or poor-risk patients with RCC by IMDC criteria, was that cabozantinib was superior to sunitinib. The primary endpoint was PFS by investigator assessment.

Since then, the study has also been validated by independent observers and assessments. The results still hold true that, in terms of PFS and response rate, cabozantinib is a superior choice to sunitinib for patients with intermediate- or poor-risk RCC by IMDC criteria.

How have the CABOSUN trial data impacted clinical practice?

This trial has already been in the National Comprehensive Cancer Network guideline category to be endorsed. It offers a clinical option for patients who fit the IMDC intermediate- or poor-risk criteria, which is by far the majority of the patients, at about 80%. Cabozantinib for those patients is a valid option, especially for those who are not able to go on any of the alternate available options, including immunotherapies, which are also a big class of drugs for these patients. Some reasons for contraindications to immunotherapies are autoimmune diseases or previous organ transplants, which make it very risky to go on checkpoint inhibitors. For those patients, particularly, [cabozantinib] is pretty much the only option.

Does this trial leave any unanswered questions?

Absolutely. This is a randomized phase II trial. Ideally, we want to be validated in a phase III setting. There has been a second-line, phase III trial comparing cabozantinib to everolimus (Afinitor) called METEOR, and the [data] were significant for overall survival (OS). However, at this point, CABOSUN is a phase II trial and it still has strong data for supporting cabozantinib use. More data are needed, especially with all the changes in the first- and second-line spaces, particularly with the immunotherapy combinations. There is an ongoing trial of cabozantinib in combination with nivolumab that is expected to read out very soon. The field may completely change [with those data].

Beyond cabozantinib, what does the current landscape looks like regarding TKIs in metastatic RCC? How do these agents compare with one another? 

TKIs have a continuing role in RCC therapy, either as a single agent for this favorable-risk category where they appear to be superior to immunotherapy, and also in combination with immunotherapy. There have been 2 combinations already FDA approved for frontline therapy: axitinib plus avelumab and axitinib plus pembrolizumab. There are a couple of others that are expected to read out, particularly lenvatinib (Lenvima) with pembrolizumab as well as cabozantinib with nivolumab. [TKIs] have a role in favorable RCC by itself, but also in combination in intermediate- and poor-risk patients, which is going to most likely expand in the upcoming years.

In favorable-risk RCC, among other options, TKIs can be used as single-agent therapy. In intermediate- and poor-risk RCC, we probably have to use [TKIs] in combination with immunotherapy because those have been proven to be superior to monotherapy. In that sense, the context in which they are used is critical to evaluating whether we go with monotherapy or combination therapy.

There are some class-specific toxicities among all of these TKIs. Some of them result from their mechanism of action, which is a measure of VEGFR inhibition, including hypertension, rashes on the hands and feet, gastrointestinal (GI) toxicities like diarrhea and mucositis, dysphonia, transaminitis, liver toxicity, and some cardiac toxicity. The frequencies are a little higher or lower with each particular drug, but largely these are shared [with the class of VEGF TKIs]

There are some differences in how frequently adverse events occur for 1 class of toxicities versus the other. For example, tivozanib (Fotivda) can cause more dysphonia and axitinib can cause more diarrhea; sunitinib can cause more diarrhea and [other] GI toxicities. There are some signals and toxicities that may be more important to choosing one [agent] over the other in a particular patient. The schedule is also a little different the way [these drugs] are given. Sunitinib is a 4-weeks-on/2-weeks-off schedule. Axitinib is a short-acting drug so it's given twice daily, and the dose can be varied up and down from the starting dose. The other drugs are [taken once daily].

Could you highlight the impact of combinations with TKIs and immunotherapy? 

The KEYNOTE-426 [trial] compared axitinib plus pembrolizumab with sunitinib. That was a positive study for its primary endpoint; it was positive for OS as well as for PFS, which led to the FDA approval of the combination in all IMDC prognostic groups. It's a valid option.

On the other hand, as you would expect, there was a little signal showing that toxicities [for these combinations] were greater than single-agent therapy, particularly with some liver toxicities. Axitinib and pembrolizumab both have some overlapping toxicity in [the liver] as well as [some overlapping] GI toxicity. These sometimes have to be managed very carefully in the clinic and the individual patient, because it can be tricky. Axitinib is good; the half-life is very short. By holding axitinib, we can get a quick answer whether [the toxicity] is from axitinib or whether it is an immune-mediated [toxicity] from pembrolizumab.

[The phase III data with] avelumab/axitinib was also presented, and that study did not meet OS. The data were not mature yet and did not show overall difference; that [OS benefit] could still happen in updates that could be presented at upcoming conferences. It did meet one of its endpoints, which was PFS, and that led to the FDA approval of that [combination], as well. Avelumab is given every 2 weeks, and pembrolizumab is given every 3 weeks. There is a scheduling difference, which could be of importance.

Is the paradigm shifting towards combinations for all patients?

Combinations have already started to occupy a greater share of the number of patients being treated. Monotherapy will still have its role, but it's probably going to be diminishing. The [current TKI/immunotherapy] combinations address 2 different classes of drugs combined—the VEGFR pathway as well as [the PD-1/PD-L1] pathway&mdash;which offers a simple combination. Both agents in their respective classes were always active against kidney cancer.

The bigger questions in the upcoming years is what to use after a TKI and immunotherapy combination. What do we go to next? Maybe it's a separate class of drugs. There are some that are being tested in trials, such as metabolic inhibitors, glutamine inhibitors, and arginine-based inhibitors. There are also new molecules attacking HIF1A, so those could be classes of drugs that would have to be explored for post-combination progression.

Choueiri TK, Hessel C, Halabi S, et al. Progression-free survival (PFS) by independent review and updated overall survival (OS) results from Alliance A031203 trial (CABOSUN): Cabozantinib versus sunitinib as initial targeted therapy doe patients (pts) with metastatic renal cell carcinoma (mRCC). 

. 2017;28(suppl_5):v605-v649. 10.1093/annonc/mdx440.

Choueiri TK, Hessel C, Halabi S, et al. Cabozantinib versus sunitinib as initial therapy for metastatic renal cell carcinoma of intermediate or poor risk (Alliance A031203 CABOSUN randomised trial): progression-free survival by independent review and overall survival update. 

. 2018;94(115-125). doi: 10.1016/j.ejca.2018.02.012.

Ajjai Shivaram Alva, MBBS, highlights ongoing advances made in the treatment of patients with metastatic renal cell carcinoma.

Single-Agent and Combo Approvals Lead to Personalized Approach in RCC

Shirish M. Gadgeel, MD, MBBS, professor, University of Michigan Medicine, discusses the updated results of the phase III KEYNOTE-189 trial in metastatic nonsquamous non—small cell lung cancer (NSCLC).

In the KEYNOTE-189 trial, patients were randomized to receive pembrolizumab (Keytruda) and chemotherapy versus chemotherapy alone. The median overall survival rate of patients with pembrolizumab added to chemotherapy was 22 months compared with 10.9 months for patients with chemotherapy alone.

At 2 years, 45.5% of patients who received pembrolizumab were alive compared with 29% of patients who received chemotherapy alone, showing a 16.5% improvement in survival with pembrolizumab. Progression-free survival was 9 months with pembrolizumab compared with 5 months for chemotherapy alone. These improvements were observed across all PD-L1 subsets, including patients whose tumor proportion score was 0. No additional safety signals were identified in this study, according to Gadgeel.

Videos

Shirish M. Gadgeel, MD, MBBS, professor, University of Michigan Medicine, discusses the updated results of the phase III KEYNOTE-189 trial in metastatic nonsquamous non-small cell lung cancer (NSCLC).

Dr. Gadgeel on Updated KEYNOTE-189 Data in NSCLC

Desire to undergo a contralateral prophylactic mastectomy (CPM) has been rising in patients diagnosed with breast cancer in recent years. CPM is discouraged for patients without an elevated risk for a second primary breast cancer, as per surgical guidelines.

A population-based survey was conducted to examine the association between patient report of surgical recommendation against CPM and to what extent it was discussed with the surgeon. Three outcomes were considered: patient satisfaction with surgery decisions, receipt of a second opinion, and receipt of surgery by a second surgeon.

“Surgeons have been concerned about the rise in the use of this procedure, which is quite morbid—the removal of both breasts. They are not enthusiastic about performing this procedure in the tens of thousands of women who will receive it this year, and they are concerned about how to have this discussion with patients,” said lead author Steven J. Katz, MD.

Katz says that surgical recommendation against CPM did not seem to push patients to seek a second opinion or to switch surgeons. Although, findings did show that patients were less satisfied with surgical decision if the surgeon who recommended against CPM did not have a substantive discussion about it.

 Could you provide some background on the rationale behind this study?

, Katz, professor of medicine and health management and policy at the University of Michigan, discussed his study of patient reaction to surgeon recommendations about CPM.

 CPM for women with early-stage breast cancer is a major issue that has evolved over the past 5 to 7 years and the number of the women undergoing this most extensive surgical treatment has increased rather dramatically. This is probably related to more attention given to the procedure from famous people who got it, and with more women getting CPM in the community—newly diagnosed patients know of a daughter or mother or friend who have had it and are very happy with the fact that they feel that they are completely free of any future possibility of having the caner. The problem with this mindset is that many women getting CPM are at average risk for a second primary cancer. The risk of developing a secondary breast cancer is so low, given all of the other reasons, that CPM in average-risk women does not confer any benefit with regard to survival or even distant recurrence. Additionally, reconstructive surgery means more days lost at work and long-term quality-of-life issues related to not having the natural breast.

The study that we did was a large survey of patients, shortly after diagnosis, in Georgia and Los Angeles county, and we asked what their surgeons recommended and what their reaction was along 3 lines: did they get a second opinion, did they go to a different surgeon to get the operation if their first surgeon recommended against it, or did the suggestion affect their satisfaction with overall surgical decision making.

What we found was pretty reassuring—about one-third of women reported that their surgeons recommended against CPM. That report was not associated with a second opinion or losing the patient to a second surgeon. There was a little bit of dissatisfaction&mdash;women were more dissatisfied with their overall surgical decision, not based on the recommendation alone, but whether that was well discussed or not. If the recommendation was not well discussed, those patients were somewhat more dissatisfied with the overall surgical decision.

The conclusion of the paper was that there was a substantial amount of patients reporting that their surgeons are recommending against this most aggressive treatment, that it doesn't seem to be motivating patients to go to another surgeon, and that dissatisfaction with decision-making seems to be tied with the adequacy of discussion over exactly what recommendation is made. The pushback against this surgery does not seem to be causing a great discourse in the clinical encounter.

How do you feel these findings will impact surgical decisions moving forward?

Moving forward, we need to have these discussions and those discussions need to be a little more proactive then they have been in the past. We did not have to worry about this 7 years ago before women were much more interested than they are now.

I think that this is a very important issue. What we have learned in our research is that patients often desire the most extensive treatment, whether it is surgery or medicine. I think that surgeons in the nation are concerned about this, as well as how to manage this extensive treatment with their patients. Overtreatment needs to be addressed in patients who want to undergo a more extensive treatment than is necessary, because that will actually bring more harm than good.

What would you suggest surgeons focus on to help guide patients in a more proactive way?

The rise in desire for CPM is a good example of surgeons recalibrating, revisiting how they want to approach an issue. One of the most important things is to talk to women about this procedure, and what the marginal benefit is to them, and try to help them resist their fear of disease and treatment that might be motivating them to seek everything that they can possibly get now, so that they can get home to their families. The problem is, getting everything now can actually result in more harm than good because most patients do not need everything. CPM, in most surgeon's eyes, is overtreatment, and they have to talk to their patients more so their patients understand this natural tendency to desire more extensive treatment.

I would suggest a couple things—many patients increasingly rely on their doctors because this type of information is so complex. Let that happen, it is okay, let patients seek out navigation by the surgeons and medical oncologists. Also, decision making of this nature is not a surgical emergency, there is time. When there is not adequate time to talk, the immediate reaction is “take them away and get me home.” We want to resist this immediate reaction by spending time with patients, slowing the process down&mdash;let them ponder what the surgeons actually have to say about the pros and cons of this procedure.

I also recommend that patients ask their surgeons to summarize their recommendations and why, and audiotape it and listen to it a few times. Turn to your surgeon at the end of the meeting and say, “I’d to hear your recommendations against this surgery and why, and I’d like to record it on my phone.” And then patients can walk away and come back to that information. It is also good for patients to have someone in the room with them to clarify any questions because it is hard to ask questions when you are in the room alone right after diagnosis. Most women with breast cancer have someone in the room with them, and most women report that that person is taking notes for them—which is another good thing because that person is not going through the disease, and the notes can be much more unbiased and be more reflective about what can happen next.

Katz SJ, Janz NK, Abrahamse P, et al. Patient reactions to surgeon recommendations about contralateral prophylactic mastectomy for treatment of breast cancer [published online April 5, 2017]. 

Steven J. Katz, MD, discusses his study of patient reaction to surgeon recommendations about contralateral prophylactic mastectomy for patients with breast cancer.

Expert Discusses Recommending Against Prophylactic Mastectomy

David Arenberg, MD, associate professor, Department of Internal Medicine at the University of Michigan, discusses preliminary results of a low-cost intervention to improve tobacco cessation practices within a large university health system.

This study was more of a quality-improvement initiative than a research study, states Arenberg, and explored What the University of Michigan health system providers did in terms of the basics of tobacco cessation.

The US Preventive Services Task Force recommends the 5 basics, which include asking every patient about tobacco smoking, advising every smoker to quit, assessing the willingness to quit, offering assistance to quit either in terms of motivational interviewing or pharmacotherapy, and arranging a follow-up.

Dr. Arenberg on Low-Cost Intervention to Improve Tobacco Cessation for Lung Cancer

 evaluated racial and ethnic disparities in guideline-based care for women with locally advanced cervical cancer using the National Cancer Database.

The intent for this study, said lead investigator Shitanshu Uppal, MD, was to understand the disparities of care, mainly, why certain women are not receiving standard of care for cervical cancer. Additionally, if a woman is not given standard of care, the reason is not included in her chart and is therefore excluded from that entry into the National Cancer Database.

“We never document a clear reason as to why a particular therapy was not done, which is a big part of healthcare that is missing right now,” said Uppal.

In a cohort of 16,195 patients, the rate of guideline-based care was 58.4% (95% CI, 57.4-59.4) for non-Hispanic white women, 53% (95% CI, 51.4-54.9) for non-Hispanic black women, and 51.5% (95% CI, 49.4-53.7) for Hispanic women (

<.001). As per a propensity score-matched analysis, women who received guideline-based care had a lower risk of mortality than those who did not (adjusted HR, 0.65; 95% CI, 0.62-0.68).

The study found that racial and ethnic disparities in the administration of guideline-based care were highest in high-volume hospitals.

Please provide an overview of this study.

, Uppal, assistant professor of obstetrics and gynecology at Michigan Medicine, discussed the study and the need for a more comprehensive registry process for patients with cervical cancer.

One of the areas where I am focusing now is at the intersection of disparities and the utilization of standard of care. What I fundamentally believe is that in order to reduce a disparity, [it is necessary to] look at the quality of the monitoring. That means, asking if everyone receives standard of care quality of care. If that is remedied, then maybe we will see a decline in disparity of care.

We used the National Cancer Database. We looked at information from database from 2004 to 2012. The idea was to basically get patients into 2 cohorts—whether they got the care or did not get the care&mdash;and the ones who did not get the care we looked at what component of their care was missing.

What do you do think would be viable next steps to remedy these shortcomings?

What would you like your fellow oncologists to take away from this study?

Is there anything else you’d like to mention?

We started brainstorming how to answer the question of why guideline-based care was so low, and what should we do next. And we kept coming back to the point that not knowing what is going on is such a big problem. You can imagine a scenario where a patient with cervical cancer has to come to the hospital every single day to get radiation for 5 weeks. So, if we got 200 of these women, and 20 of them said, “Well, I didn't have a car to come to the hospital every single day” is different than them saying, “Oh well, we weren't told that coming everyday is as important as we thought it is.” How we design something to fix this problem will depend on what exactly is the problem. Our paper is just processing that there is a problem. 

What is urgently needed based on these data is that whenever the standard of care is not followed, physicians need to actually document the reason. This is not only needed in cervical cancer, but other cancers as well. Every hospital, in my opinion, should have a repository of why certain patients were not given standard of care. In breast and colorectal cancer, for example, single institutions have looked at what is the number of patients if you were dedicated to delivering patients with national comprehensive cancer network guideline—based care, the rates are somewhere in the range of 75% to 90%. The actual rates are extremely low—60% in the best case scenario. Again, what will be the next step? To find out why is it that 40% of the people are not getting what they should be getting. 

Two points. One is that we have to be mindful as to why we are not doing guideline-based care and the second is this misperception in the oncology world that patients are not getting the standard of care because they are going to low-volume hospitals. What we found in our study, is that even when you went to a high-volume hospital, even though you got care which was better than low-volume hospitals, not everybody got standard-of-care. Even in the best-case scenario, we are getting to 65% of white women in high-volume hospitals receiving standard of care. So, just because somebody is doing something many times, doesn’t mean that they are doing it correctly.

There is a related story to this that came out in

based on a study in the journal Cancer that looked at mortality statistics. We look at how many out of 100,000 actually get a particular cancer and how many die. What they did was recalculate that metric by excluding women who already have their uterus taken out. And because of that, the number of patients who had cervical cancer was extremely high compared to what we have the estimates for. One of the facts is that African-American women get hysterectomies more often than white women, and what ended up happening was that by adjusting the rates by excluding women who have had a hysterectomy before, the mortality in some of the African-American women was close to mortalities from cervical cancer in third-world countries. And that is huge, we are sitting in one of the largest economies and we are still having mortality rates in cervical cancer that are comparable to a third-world country, it is pathetic. This is not something we should be able to tolerate in this country. 

Uppal S, Chapman C, Spencer RJ, et al. Association of hospital volume with racial and ethnic disparities in locally advanced cervical cancer treatment.

. 2017;129(2):295-304. doi:10.1097/AOG.0000000000001819.

Shitanshu Uppal, MD, discusses a study of racial and ethnic disparities in guideline-based care for women with locally advanced cervical cancer and the need for a more comprehensive registry process.

Disparities in Guideline-Based Cervical Cancer Care Greatest at High-Volume Hospitals

Daniel Eidelberg Spratt, MD, assistant professor, radiation oncology, University of Michigan Health System, discusses the combination of immunotherapy and radiation in patients with prostate cancer.

Immunotherapy in patients who have metastatic disease of different types of cancer, have shown great response rates. There are ongoing trials that are focused on combining radiation and immunotherapy to try to release antigens so the immunotherapy knows the cancer should not exist, Spratt explains.

Prostate cancer has had less success than different tumor types, such as multiple myeloma. Some of the initial trials being done have not shown favorable results but the trials are still ongoing, Spratt states.

Dr. Spratt on Combination of Immunotherapy and Radiation in Prostate Cancer

A sharp decline has been observed in the overall rate of men receiving treatment for prostate cancer, according to the results of a study published in 

This decline is potentially attributed to recent changes in guideline recommendations that suggest that there is widespread overdiagnosis and overtreatment in the prostate cancer treatment paradigm.

The study found that population-based treatment rates declined by 42%, while rates among diagnosed men declined by only 8%.

“It was surprising to see such a big decrease,” said study author Tudor Borza, MD. “We didn’t know how much of an uptick there would be by primary care doctors in terms of decreasing their PSA screening and how that would translate to men getting treated.”

: What was the rationale for collecting these data about men with prostate cancer?

, Borza, a urologic oncology and health services research fellow at Michigan Medicine, discusses the major findings of his study and his stance on the importance of prostate cancer screening and treatment.

: We wanted to look at this particular rate of treatment because, over the last decade or so, there have been many changes in the recommendations for prostate cancer screening and the way that men with prostate cancer are treated. In our paper, we looked at the changes in national screening recommendations made by the US Preventive Services Task Force. which, in 2009, recommended against screening for prostate cancer in men older than 75. And then in late 2011/early 2012, they recommended against all PSA screenings for prostate cancer, saying that the harms from screening were greater than the harms from treatment. Obviously, there’s a lot of press that surrounded that decision, and many physicians changed the way they practice medicine because of that.

Similarly, professional organizations that guide how specialists do their jobs, like the American Urological Association (AUA), and the NCCN, also changed their screening recommendations, though not to the same degree. Most specialists and national organizations still recommend PSA screening, now in different groups of men, but they still recommend that it be done.

At the same time, because of the known overdiagnosis and overtreatment of prostate cancer, specialists started to use surveillance strategies—either watchful waiting for men who don’t have a long life expectancy, or active surveillance for men with low-risk prostate cancer. Both of these have been shown to be as effective as upfront treatment. We’ve started using these surveillance strategies with the goal of avoiding unnecessary treatment in some of these men.

What were the most significant findings from your study?

All of these things were happening over the period of time that we conducted our study. We wanted to get an idea of what the effect was on treatment from this overall change in thinking, and really try to tease out whether the screening recommendations or the use of surveillance had more of an impact on the treatment rates.

We looked at the treatment rates in the population as a whole—that’s all men who could possibly be screened for prostate cancer in our Medicare sample. We found that that treatment rate decreased by 42%. It went from 4.3 per 1000 men to 2.5 per 1000 men getting treated, and that’s a big drop.

Were these results surprising to you in any way?

Where do you stand in terms of all the controversy surrounding PSA screening?

When we looked at just the men who were already diagnosed, that decrease was only 8%—from 718 to 659 men per 1000 patients getting treated. A lot of people infer that the screening recommendations had a big impact on how many men get diagnosed and then how many men can potentially be treated. The use of surveillance had only a minor impact on that overall decrease in treatment rates.

We didn’t really have a good understanding of what the screening recommendations would do to treatment. It was surprising to see such a big decrease. We didn’t know how much of an uptick there would be by primary care doctors in terms of decreasing their PSA screening and how that would translate to men getting treated. A 42% decrease was certainly surprising.

Yes, there’s definitely a lot of controversy. I’m a urologist; we see men who often have significant disease that is going to be fatal, and in that context, not screening anyone for prostate cancer doesn’t seem to make sense to us. We know that, when PSA was introduced in the early 1990s, the incidence of metastatic disease at diagnosis of prostate cancer plummeted. So we know there is a benefit to this. But obviously, there’s plenty of overdiagnosis and overtreatment—diagnosing men who would never be symptomatic or treating men who don’t need treatment.

Are there any next steps planned following the results of your study?

What progress would you like to see in this treatment landscape in the next 5 to 10 years?

There is a middle ground here, and I think that middle ground is what the AUA guidelines recommend, that for men who we know are at a higher risk, having a discussion about what it means to have a PSA screening test and how that could potentially lead to a downstream biopsy and diagnosis of prostate cancer that may require treatment—having that conversation with a patient, and making sure they understand prior to ordering the PSA test, this is best practice, and really having the patient involved in that decision, not just making a decision as a physician alone. That is probably the best way to do it.

There are a couple next steps. Our study ended in 2012, and we now have an additional year of data, so we’ll be seeing how that trend continues and if there is a continued increase in the use of surveillance—which we expect there will be based on some other research. There are other investigators within our group that are using collaborative data, (not Medicare data, but data pooled from all the urologists in the state) looking at the use of active surveillance, which allows a different look than we’re able to do using just Medicare data and seeing what the rates of surveillance are, and how surveillance is done, and really talking with the treating urologist and figuring out what the barriers are to the use of surveillance and how we can overcome those to increase the use of active surveillance in men with low-risk disease or increase the use of watchful waiting in men who have a very limited life expectancy.

I think in the next 5 years, we’re going to get much better at risk-stratifying men—that is, figuring out which men with prostate cancer are going to be at highest risk of developing metastatic disease and dying, and that’s through the use of new tissue biomarkers as well as the advance of prostate MRI. A better way of figuring out who these high-risk patients are will allow us to provide them with more aggressive treatment upfront, so they’re the ones that are most likely to benefit. And on the flip side, it’ll allow us to spare some men who aren’t going to ever have a problem from prostate cancer from treatment. I’d like to see us push that envelope of really identifying who’s at highest and lowest risk. That’s going to allow us to provide much more accurate, tailored treatment strategies in the future.

Borza T, Kaufman SR, Shahinian VB, et al. Sharp decline in prostate cancer treatment among men in the general population, but not among diagnosed men. 

. 36, NO. 1 (2017): 108—115. doi: 10.1377/hlthaff.2016.0739.

A sharp decline has been observed in the overall rate of men receiving treatment for prostate cancer.

Prostate Cancer Treatment Rates Drop Following Changes in Screening Recommendations

In the current treatment landscape of HPV-positive oropharyngeal squamous cell carcinoma (OPSCC), there is a significant lack of biomarkers to predict recurrence. Additionally, as Matthew E. Spector, MD, notes, the incidence of OPSCC continues to rise.

“Due to HPV, people are getting more and more of these types of cancers, and hopefully that will go down once more people get vaccinated, but right now, we’re on this big upswing that’s probably going to keep going up,” said Spector, who is the lead author of a new biomarker study published in 

In the study, researchers found that patients whose oropharyngeal cancer recurred had higher levels of antibodies for 2 proteins, E6 and E7, which are found in HPV-driven cancers. These findings highlight the potential for a novel, blood-based marker that could predict when cancer is likely to return.

: Please discuss the lack of biomarkers in head and neck cancer, and how that affects the treatment landscape.

, Spector, an assistant professor specializing in otolaryngology at the University of Michigan Medical School, discussed the results of this study as well as the pressing need for biomarkers in this patient population.

: Oropharynx cancer is one of the only types of cancer that is really increasing in incidence, especially in head and neck cancer. Due to HPV, people are getting more and more of these types of cancers, and hopefully, that will go down once more people get vaccinated, but right now, we’re on this big upswing that’s probably going to keep going up. These patients are usually younger, they’re healthier, and they have less smoking and drinking history. When we saw this, we needed a way to try to predict which patients would fail therapy, because most patients do pretty well.

Biomarkers in cancer are always a little tricky. There are some really good ones out there. Prostate cancer has a really good blood-based biomarker, as does thyroid cancer. But for head and neck cancer, we’ve tried a lot of different things, but we haven’t been able to detect it.

How was your study conducted, and what were the most significant findings?

What’s unique about this cancer is that there are actually viral oncoproteins that are circulating in the blood at some point, so we used that premise to develop this test. The test basically looks at antibodies against those viral oncoproteins, and they’re called E6 and E7, and we’re able to detect those in patients who are developing recurrence where their antibody levels are actually going up.

The patients that we used for this trial were before my time here at the University of Michigan, but 1 thing we’ve done really well as a group is to collect samples on everybody. We collect blood samples every couple of months, we collect tumor samples when patients initially develop cancer, and then we store these to do studies like this.

We looked back at patients, who were treated from approximately 2000 to 2010, and we looked at their blood samples, and then we divided them into 2 groups: patients who recurred and patients who didn’t. Then we used their blood samples to measure these antibody levels.

So this is measured more on a patient-by-patient basis, rather than a one-size-fits-all approach?

Are there any next steps planned following these results?

Are there any other related trials looking for biomarkers in this particular cancer type that you’d like to discuss?

It was very interesting that, before anyone received any treatment at all for their cancer, everyone had high antibody levels—which is expected. Everyone has these proteins in their blood, so after treatment, or when you were treated, everyone all saw those levels go down. But the interesting thing was that, for patients who developed recurrence, their antibody levels went back up again&mdash;especially the E7 antibody. So if you take a patient at baseline, and you track their antibody levels, they go down and then up, and that uptick is a chance for us to detect recurrence before we’re actually finding it in the patient.

Yes, this is definitely patient-specific. My antibody levels might be different than yours, and yours might be different than someone else’s. But if you track them over time within a patient, the levels should definitely go down and never go back up. And everyone kind of starts at a different level, too, so it’s a very personalized way to watch for cancer recurrence.

We wrote a phase II clinical trial that we’re currently conducting, and we’re also in collaboration with other groups to look at bigger sets of patients with this type of cancer to see if we can develop other markers.

This one is specific for HPV-positive cancer, but we have a second trial that’s looking at all head and neck cancers, and it’s called MiOTOSeq. That trial is looking at genomic markers, meaning patients who have a gene mutated in their type of cancer, and it’s something we can follow or find a treatment for that may not be specific to head and neck cancer.

What would you like to see in the next 5 to 10 years in the development of biomarkers in this space?

Are there any major challenges standing in the way of that kind of revolution?

Like right now, there are maybe a dozen drugs approved for head and neck cancer, but there are thousands of drugs out there that could potentially be used in one of our patients, we just don’t know it yet. So the premise of MiOTOSeq is to sequence patients’ cancer genome, find out where the mutations are, and see if there are any druggable targets against this particular cancer—and maybe it’s not even a drug used for head and neck cancer, maybe it’s traditionally used for something else.

I would like to see blood-based biomarkers used almost in conjunction with a physical exam to follow cancer patients. If you look at the NCCN guidelines, patients are supposed to be checked every 2 to 3 months in the first year. But if they live far away, maybe they could, instead, send a vial of blood every 2 or 3 months, and then we can test their blood and see if it’s clear, and we can possibly change how often we see them, or maybe we detect something and bring them in sooner for a scan. A blood test could revolutionize the way we follow patients after treatment and how we scan them, or how we decide which imaging studies to use, based just on a small test.

I think that getting large numbers of patients together to do research is always hard. Head and neck cancer doesn’t have as many patients as maybe breast cancer or colon cancer, and so some of these other cancers have already paved the way for this type of research.

Spector ME, Sacco AG, Bellile EL, et al. E6 and E7 antibody levels are potential biomarkers of recurrence in patients with advanced stage human papillomavirus positive oropharyngeal squamous cell carcinoma [published online November 21, 2016]. 

In the current treatment landscape of HPV-positive oropharyngeal squamous cell carcinoma, there is a significant lack of biomarkers to predict recurrence.

Novel Biomarker May Predict Recurrence in HPV+ Oropharyngeal Cancer

	University of Michigan Comprehensive Cancer Center

	Professor, Medicine and Health Management and Policy

As genetic testing becomes increasingly available, there will be a growing gap between the wide availability of testing and the relative importance of results to treatment decisions. In the current environment, there’s more promise in precision medicine than practical applications in the exam room. Multigene panel testing is increasingly available, but we don’t fully understand how to best incorporate results into treatment recommendations for patients with breast cancer.

As a result, patients newly diagnosed with breast cancer and their doctors face a conundrum in the exam room: how to efficiently incorporate increasingly complex clinical information into treatment decision making.

The demand is growing for genetic testing. More than a quarter of patients newly diagnosed with breast cancer undergo genetic testing now. That rate has been increasing, and recent studies suggest it could be even higher.

Our study of 1536 breast cancer survivors published this year in the Journal of Clinical Oncology found that 35% of patients had a strong desire for genetic testing.

 Many of the women who reported strong interest were at low risk of having a mutation and might not be typical candidates for a discussion about genetic testing.

But whether results of genetic testing show a mutation or not, what does it mean for physicians recommending treatment options to patients and for patients trying to understand complex treatment options and risk to decide how to treat their cancer? We need to change both the way genetic tests results are reported and, more importantly, how results are incorporated into treatment deliberation for patients newly diagnosed with breast cancer. After diagnosis, patients face a rapid escalation of treatment decisions navigated by different specialists. We need to allow more time for deliberation and a better way to incorporate increasingly more complex genetic and genomic information into the process.

Germline genetic testing often requires discussions with genetic counselors. Patients need a stepwise approach to deliberation and ought not to rush the process. We don’t honor enough the process and time patients need for treatment decision making.

This can be seen in the recent uptick in women choosing contralateral prophylactic mastectomy (CPM). A 2014 study in 

found that 70% percent of women who have CPM have no clinical indications, such as a family history of breast or ovarian cancer or a mutation found on genetic testing.

 In fact, many of these women were candidates for breast conservation. It’s striking that so many women are receiving much more extensive surgery than needed to treat their disease.

Women diagnosed with breast cancer are naturally eager to do everything in their power to fight the disease. So many patients confide that they just want to do everything they can to be there for their children. It is up to us, as doctors, to make sure they understand which treatments are really going to do that, and which actions might seem heroic but are actually not expected to improve the outcomes for a typical woman with early-stage breast cancer.

Our team presented an abstract at the 2015 American Society of Clinical Oncology Annual Meeting that found nearly half of 1949 breast cancer survivors surveyed said they considered CPM.

 Of those who considered it, only 37% knew that the more aggressive procedure does not improve survival for women at average risk of a second cancer. Further, we found that women’s perceptions of their surgeon’s recommendation played a big role in the decision to have CPM. Only 4% of women who said their surgeon recommended against CPM had the procedure. But even among patients who did not have a genetic mutation or strong family history to motivate the decision for CPM, 23% who said their surgeon didn’t recommend for or against CPM went on to have the aggressive surgery.

This research indicates that patients are coming away with perceptions that really require adjustments. Doctors need to address the jaw-dropping gaps in patient knowledge of CPM benefits and the perception of what their surgeons told them.

The University of Michigan Comprehensive Cancer Center leads an interdisciplinary group of investigators from across the country seeking to understand and improve how patients and their providers communicate and make decisions about cancer treatments.

Research Team (CanSORT) has a grant from the National Cancer Institute, part of which includes building a decision tool to help women with breast cancer fully understand their treatment options and the risks involved.

Part of the issue is in how different healthcare providers frame information about risk. Typically, genetics experts focus on the cumulative risk of another cancer over a lifetime. This doesn’t incorporate comorbid conditions, such as heart disease, diabetes, or even the present cancer diagnosis. Meanwhile, oncologists recommending treatment for the current cancer talk about 5- to 10-year survival rates and they do consider other health risks.

Patients are stuck in the middle, trying to make sense of it all. As healthcare professionals, we need to do a better job of framing this discussion in a patient-centered, coherent way. CanSORT investigators are currently in the midst of a survey called iCanCare, and are beginning to analyze responses from 7500 breast cancer survivors on issues related to treatment decision making. The team is also completing an agreement that would involve looking at patterns of genetic testing among a very large sample of patients with breast cancer. Going forward, we believe breast cancer will be the tracer condition to show how genetic testing can influence treatment decision making and improve patient health.

			Jagsi R, Griffith KA, Kurian AW, et al. Concerns about cancer risk and experiences with genetic testing in a diverse population of patients with breast cancer. J Clin Oncol. 2015;33(14):1584-1591.

			Hawley ST, Jagsi R, Morrow M, et al. Social and clinical determinants of contralateral prophylactic mastectomy. JAMA Surg. 2014;149(6):582-589.

			Jagsi R, Kurian AW, Griffith KA, et al. Genetic testing decisions of breast cancer patients: results from the iCanCare study. J Clin Oncol. 2015;(suppl; abstr 1541).

As genetic testing becomes increasingly available,
there will be a growing gap between
the wide availability of testing and the relative
importance of results to treatment decisions.