Treating older patients with HER2-positive or triple-negative breast cancer (TNBC) must include more quality of life considerations and different types of survival calculations, even when the basic tools and treatment regimens are similar to those used in younger patients, according to a talk at the 2017 Lynn Sage Breast Cancer Symposium.

"The real question isn't how old the patient is, but what their life expectancy is," said geriatric oncologist Hyman Muss, MD, of the University of North Carolina School of Medicine, at the symposium, which was sponsored by Northwestern University's Robert H. Lurie Comprehensive Cancer Center. "Then you calculate the risks and benefits of toxicity, and then put it all together with the defining goals of treatment. And the goal is not always longevity."

For example, while younger patients can still function reasonably well during chemotherapy and will have time to recover from side effects, older patients may be debilitated to the point where they need to move from independent to assisted living, or even full nursing home care. Moreover, patients older than 65 have significantly greater risk of being hospitalized for side effects from chemotherapy. One study showed that for some regimens, their risk was triple that of patients younger than 65.

"This is the worst thing for an older patient," Muss said. "It can be the beginning of going to a skilled nursing facility, falling, and having numerous other problems." Staying out of the hospital may take priority over gaining the benefits of chemotherapy, which may be marginal any way if the patient's tumor is 1 cm or smaller, Muss said.

More than 40% of new breast cancer diagnoses are in women 65 and older. In the United States, the median age for a breast cancer diagnosis is 62 years and the median age of death is 68 years, Muss said. But there are also 3 million breast cancer survivors who are older than 65, according to the SEER database.

For older patients, Muss said, clinicians must ask 2 questions that they might not ask for younger ones:

What is the patient's life expectancy without cancer?

Using a life expectancy calculator from the University of California at San Francisco,

 Muss walked through a comparison of 2 patients in their late 70s. The first had excellent health according to her own assessment, had no health issues besides cancer, and lived entirely independently. Her 5-year all-cause mortality risk was between 4% and 23%. The second, a former smoker, had diabetes and COPD and one hospitalization in the past year, rated her own health as fair. Her 5-year mortality risk was 69%.

 a tool from the United Kingdom’s National Health Service that helps clinicians and patients evaluate the benefits of various  treatment options following breast cancer surgery. It presents survival estimates with and without adjuvant therapies. The model takes into account all-cause mortality, and recommends adjuvant therapy only for patients with a 5% or greater chance of surviving for 10 years. If it's less than 3%, adjuvant therapy is not offered at all because the side effects exceed the potential benefit.

While healthy older patients can make treatment choices similar to younger patients, and truly frail ones may need only palliative care, there's an “in between" group that can be treated successfully with some preparation to address their potential vulnerabilities. For example, Muss strongly recommended a cardiology consult if an older patient has risk factors for congestive heart failure. Proactive beta-blockers or ACE inhibitors may help reduce toxicity during treatment.

Muss said sentinel node biopsies might be worth the time and cost to help an older patient decide whether the benefits of chemotherapy are worth the risks and the quality of life impact, especially in cases of triple-negative breast cancers where the tumor is 1 cm or 2 cm. "If they say they are absolutely never going to consider chemo, then don't do it," he said. "But sometimes when people say they will never do chemo, it's before the fact, and when they get the results it changes their mind."

Barcenas CH, Niu J, Zhang N, et al. Risk of hospitalization according to chemotherapy regimen in early-stage breast cancer

Lee S, Smith A, Widera E, et al. ePrognosis website. https://eprognosis.ucsf.edu/. Accessed September 17, 2017.

PREDICT. Public Health England and Cambridge University website. http://www.predict.nhs.uk/. Updated May 2017. Accessed September 17, 2017.

More from the Lynn Sage Breast Cancer Symposium

The first patient should receive the same treatment as a younger patient if her cancer is likely to recur within 5 years, Muss said. The second one has both a higher likelihood of dying from something else before her cancer recurs, and a higher risk of being debilitated by chemotherapy, making the treatment decision much less straightforward.

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Treating older patients with breast cancer must include more quality of life considerations and different types of survival calculations.

Older Breast Cancer Patients Require Special Consideration

There are now several agents approved for the treatment of patients with HER2-positive breast cancer, placing the focus on the sequencing of therapies, which is largely driven by stage of disease and hormone receptor status, said Harold Burstein, MD, at the 2017 Lynn Sage Breast Cancer Symposium.

About 1 in 5 of the 250,000 new breast cancers diagnosed every year is HER2 positive. The disease used to carry a far worse diagnosis, and has gone from "worst to first" because of the success of the monoclonal antibody drug trastuzumab (Herceptin) in combination with chemotherapy, said Burstein. Disease-free survival rates have increased dramatically since trastuzumab was introduced in 1998, and without significant toxicity from the drug.  

In general, about half of diagnoses are stage I. Though HER2-positive cancers are more common in young women, they can occur at any age. "Patients with stage I disease are doing very well with simple chemotherapy and trastuzumab and need nothing further," Burstein, of the Dana-Farber Cancer Institute, said at the symposium, which was sponsored by Northwestern University's Robert H. Lurie Comprehensive Cancer Center.

Patients with more advanced disease may get additional benefits from the use of 2 recently agents: pertuzumab (Perjeta) and neratinib (Nerlynx). Pertuzumab was approved for patients with HER2-positive metastatic breast cancer in 2012 and for neoadjuvant breast cancer treatment in 2013. Neratinib was recently indicated as an adjuvant treatment of early stage HER2-positive breast cancer following 1 year of trastuzumab in July.

Burstein noted that more research needs to be done to determine where pertuzumab and neratinib are best incorporated into treatment regimens; currently, he recommends adding pertuzumab to trastuzumab and chemotherapy for stage II or III disease, and adding adjuvant neratinib at the beginning of year 2 for ER-positive, HER2-positive tumors following one year of trastuzumab. He recommends caution in using neratinib because of significant side effects. The most common is diarrhea, which was severe in almost 40% of patients.

 With the approval, the FDA recommended antidiarrheal prophylaxis with the first neratinib dose and continued for 56 days.

Regardless of the newer agents added, trastuzumab remains the starting point, Burstein said. A study of more than 4000 patients, published in 2014, showed that adding trastuzumab to chemotherapy led to a 37% relative improvement in overall survival, increasing 10-year survival from 75.2% to 84%. The 10-year disease-free survival rate increased from 62.2% to 73.7%. All patient subgroups benefited.

The HERA trial found that a year of trastuzumab treatment is optimal.

 A 2-year course did not improve disease-free survival and was associated with more side effects. However, the PHARE trial,

 published in 2013, found that 6 months on trastuzumab was almost as beneficial and should be considered in areas of the world where adequate supplies of the drug are an issue, Burstein noted.

Burstein believes, based on his clinical experience, that trastuzumab works even better on HER2-positive tumors than published studies suggest, and that some of the patients studied may not actually have had HER2-positive disease.

"Our pathology has gotten much better and we can more reliably identify who really has HER2," he said, though he notes that accurate identification of HER2 is "the single most discussed" topic among Dana-Farber's tumor board. He expects that future studies with more precise pathology will bear out his clinical experience.

Burstein also suspects that trastuzumab may be somewhat overutilized because of "fear of missing out" when equivocal pathology results suggest HER2-positive disease but do not confirm it. "We have invested too little in gauging which tumors truly respond to treatment." He also called for greater investment in quality assurance in immunohistochemistry testing.

Chan A, Delaloge S, Holmes FA, et al. Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. 

http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00551-3/abstract

Perez EA, Romond EH, Suman VJ, et al. Trastuzumab plus adjuvant chemotherapy for humanepidermal growth factor receptor 2—positive breastcancer: planned joint analysis of overall survival from NSABP B-31 and NCCTG N9831. 

. www.scribd.com/doc/316400360/liposarkom. 2014;32:3744-3752.

Goldhirsch A, Gelber RD, Piccart-Gebhart M, et al. 2 years versus 1 year of adjuvant trastuzumab for HER2-positive breast cancer (HERA): an open-label, randomised controlled trial. 

. doi.org/10.1016/S0140-6736(13)61094-6. 2013;382(9897):1021-1028.

Pivot X, Romieu G, Debled M, et al. 6 months versus 12 months of adjuvant trastuzumab for patients with HER2-positive early breast cancer (PHARE): a randomized phase 3 trial. 

. www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70225-0/fulltext. 2013;14:741-748.  

Studies also showed that trastuzumab is most effective when it is begun concurrent with chemotherapy rather than sequentially. Some studies suggest that chemotherapy will become less important as targeted therapies improve, Burstein said, though he doesn't anticipate being able to bypass chemotherapy altogether.

The sequencing of therapies for patients with HER2-positive breast cancer is largely driven by stage of disease and hormone receptor status. 

Stage, ER Status Guide HER2 Therapy Selection in Breast Cancer

Patients have a hard time with artificially induced menopause and some research suggests it may have a negligible effect on the success of their treatment, said Ruth O'Regan, MD, division chief of hematology and medical oncology at the University of Wisconsin. She spoke Friday at the 2017 Lynn Sage Breast Cancer Symposium, which is sponsored by Northwestern University's Robert H. Lurie Comprehensive Cancer Center.

Breast cancer in younger women needs a different adjuvant treatment strategy from that used in post-menopausal women, but it may not have to include suppressing ovarian function, according to Ruth O'Regan, MD, at the symposium.

"We need to home in on getting a biomarker for who needs ovarian suppression," she said, noting that among women under 35, 20% stop taking the associated endocrine therapy because the side effects are too onerous. However, as long as they continue to take tamoxifen as prescribed, some studies show equivalent survival and recurrence rates.

Only about 1 in 5 new cases of breast cancer between 2009 and 2013 were in women under 50, according to SEER data, but while relapse-free survival rates are virtually identical for all age groups over 40, rates are significantly lower for women younger than 40 (Azim, Clin Ca Res 2012;18:1341-51).

There is some sentiment that breast cancer in younger women is a different disease, O'Regan said, but the difference is primarily that premenopausal women are more likely to have triple-negative breast cancer and less luminal A cancer. The overall adjuvant regimen recommendations are currently the same for both age groups, except that for the younger group, they include ways to preserve fertility and minimize side effects from longer-term use of tamoxifen or other agents.

O'Regan reviewed research for several adjuvant regimens, including tamoxifen alone, tamoxifen with ovarian function suppression (through oophorectomy, radiation, or use of LHRH agonists), and exemestane with ovarian function suppression. Results of the Suppression of Ovarian Function Trial (SOFT) and Tamoxifen and Exemestane Trial (TEXT) showed that the regimens were similar in effectiveness among women who had not had chemotherapy, but they differed significantly in the number of side effects. Exemestane was associated with more musculoskeletal problems and osteoporosis—2 side effects that O'Regan said are particularly problematic for younger women who may be on these treatment regimens much longer.

The SOFT study specifically compared tamoxifen with and without ovarian suppression. The 5-year freedom from breast cancer rate was 95.8% for those treated with tamoxifen alone versus 95.1% and 97.1% for tamoxifen or exemestane plus ovarian suppression. In the 3 groups, respectively, there were 6, 7, and 3 distant recurrences at 5 years.

While there was almost no difference in freedom from breast cancer or freedom from distant recurrence among women who not received chemotherapy, ovarian function suppression significantly increased the risk of hot flashes, sweating, insomnia, osteoporosis, and hypertension, among other symptoms. O'Regan noted that patients might be at risk of developing premature coronary artery disease as well.

However, for women who had had chemotherapy, both studies showed clear improvement in recurrence rates from including ovarian function suppression as part of the adjuvant regimen.

Those treated with tamoxifen alone had a 78.0% 5-year freedom from breast cancer rate compared with 82.5% and 85.7% for those treated with ovarian suppression and tamoxifen or exemestane, respectively. The freedom from distant recurrence rate was 83.6% for tamoxifen alone and 84.8% and 87.8% for those treated with ovarian suppression and tamoxifen or exemestane, respectively. When compared with tamoxifen alone, these were statistically significant.

"Given the added toxicities [of ovarian function suppression], we need a better way of working out which patients need this approach," O'Regan said.

Several areas still require additional research, O’Regan pointed out. Specifically as it comes to biomarkers for selecting ovarian function suppression. Right now the progesterone receptor and the Ki-67 protein have both shown some promise as biomarkers, but more work is needed.

Additionally, she noted, 10-years of endocrine therapy, which has been shown to be superior to 5 years, has not yet been compared to ovarian function suppression plus endocrine therapy, also warranting further study.

Patients have a hard time with artificially induced menopause and some research suggests it may have a negligible effect on the success of their treatment.

Ovarian Suppression Individualization Warranted in Breast Cancer

Multigene panel testing offers a new but often puzzling tool for breast cancer treatment, since the results are often difficult to interpret, both for relative risk and risk management, according to a talk by Mark Robson, MD, at the 19

 annual Lynn Sage Breast Cancer Symposium.

 1 and 2, but these new ones are challenging," said Robson, clinic director of the clinical genetics service at Memorial Sloan Kettering Cancer Center (MSK), at the symposium, which was sponsored by Northwestern University's Robert H. Lurie Comprehensive Cancer Center.

Figuring out how a certain genetic result might change not only the type of intervention but its timing is the chief challenge. Robson recommended using available data to put each patient on an "age-specific spectrum of risk," adjusting the timing of interventions to match the patient's risk of disease relative to the general population. For example, if a woman in the general population should start screening mammograms at age 40, a woman carrying the 

 gene variant has the same level of disease risk at age 30, and should start having screenings earlier.

Robson's presentation covered nine genes associated with moderate cancer risk (with relative risk levels between 2 and 5): 

CHEK2, ATM, PALB2, BRIP1, RAD51C, RAD51D, BARD1, NBN

, and the Lynch genes. A review of available studies has revealed a mixed picture. For example, 

 overall is associated with about the same level of risk, 2.3 to 2.4, as having one first-degree relative with breast cancer. However, some 

These are far from the only possibilities, of course. Tests are available for dozens of gene variants that may make some contribution to breast cancer risk, either alone or in combination with other genes or risk factors. Some represent a low risk of breast cancer but elevated risk for ovarian cancer—or vice versa. Some don't represent any increased risk until the patient hits a certain age, and then the risk may spike to moderate or high.

Robson said clinicians must answer 2 questions as they expand the use of multigene panels in their practices. First, are the results "actionable": is the association large enough and robust enough to change a treatment recommendation? And second, do they have "clinical utility": that is, if the test is used to direct care, do patients have better outcomes? It's too early to answer the second question with large-scale studies, but Robson said some consensus is beginning to build around the first for some gene variants.

It is likely that a number of patients have these moderate risk gene variants, if testing is completed. Reviews of commercial lab data on almost 80,000 breast cancer patients showed that several genes associated with breast cancer risk have a prevalence that's comparable to 

, showed a prevalence of 1.28%, and the prevalence of 

Robson noted that genome sequencing is still too expensive to justify a large-scale controlled study that would reliably measure prevalence in populations that don't have breast cancer, but some studies are using data from public databases like the Exome Aggregation Consortium, a broad sample of genomic data acquired for other studies, as a reasonable proxy.

"The more we do, the more complicated it gets, unfortunately," Robson said, because gene variations can have several different versions, and some mutations have a much larger effect than others.

Patients given multigene panel tests at MSK are usually referred by their physicians because of a disease diagnosis or a strong family history, though there is no standardized path and some patients self-refer, Robson said. With the increasing availability of genome sequencing and other gene assays, more patients are likely to acquire information about cancer risk genes as a result of seeking testing on their own, or being tested for something else.

Regardless of how they learn about it, what should clinicians tell a 25-year-old patient who's facing elevated risk a decade or two from now? He suggesting the following example: "We understand more about your lifetime risk, and we know that when you're 40, we need to start doing something different."

Robson added that it's important to keep in mind that the patient hasn't received a diagnosis (even though it may feel that way to her), but merely a clearer understanding of her risks.

Multigene panel testing offers a new but often puzzling tool for breast cancer treatment, since the results are often difficult to interpret, both for relative risk and risk management.

Multigene Testing Adds Complexity to Decision Making Process

Even with advancements in technology, the prospect of artificial intelligence that can treat patients with cancer still remains out of reach.

That may soon change, according to Andrew Seidman, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center (MSK), who is helping IBM develop an application called Watson for Oncology. Watson has potential to be a valuable partner in helping him process the deluge of new information in his field, he said.

"We are faced with exponentially growing data from all over the world," Seidman said during a presentation at the 19th Annual Lynn Sage Breast Cancer Symposium. "At best, I might scan some article titles at the end of a long day, but it's hard for me to stay at the cutting edge and feel I'm making optimal decisions."

Seidman said oncologists are particularly challenged to keep up with the data regarding cancer-associated genes. While genomic analysis may yield a long list of actionable cancer biomarkers for a given patient, Seidman says the list is about as useful to most oncologists as a clay tablet full of hieroglyphics when it comes to making treatment decisions. Crunching large amounts of data is where computers shine, and computer decision support will become increasingly important as genomic discoveries and new treatments proliferate.

But Watson needs to be taught how to crunch, and Seidman and his MSKCC colleagues spend a lot of time figuring out how to instill their expertise into Watson's computations. He estimates that Watson for Oncology and its team are "beyond 8th grade, but not yet in high school." For each individual case used to train Watson, Seidman estimates that a human physician needs to spend 5 to 7 minutes telling the computer everything it needs to know. While Watson may do well at aggregating research findings, it needs help understanding an individual patient's ability to tolerate a treatment.

The Watson for Oncology development team's "to-do" list is long:

Add surgery and radiation to the medical oncology care plans it has been learning so far

Incorporate new treatments and care advances

Teach Watson how to match patients to appropriate clinical trials

Create an interface for patients to interact with Watson

Improve Watson's ability to link data in the literature to treatment of individual patients

Connect Watson's treatment choices with outcomes. Though several hospitals have already availed themselves of Watson for Oncology for treatment recommendations, Seidman acknowledges that the work needs to be validated. Two basic studies need to be done. "The first level is, does Watson lead to physicians changing their preconceived treatment recommendations?" he said. "That kind of study is just beginning." The second is more difficult, though more important: measuring whether Watson's recommended treatment plans lead to better patient outcomes than treatment plans left entirely to physician discretion. "We are thinking about how you would design that kind of clinical trial," Seidman said.

While Seidman does not expect to be replaced, Watson may help him and other subspecialists share their expertise more widely than they can now. "There are only so many consultations you can give, and [having access to Watson] could democratize cancer consultations." A Watson-based consultation would lack the give-and-take that two physicians can have over the phone or in email, but the computer can link the physician to relevant literature and do comparative tabulations of outcomes for different regimens. Developments in natural language processing may enable actual dialogue someday, Seidman says.

Even now, Watson occasionally outsmarts its teachers, coming up with treatment recommendations that they recognize as superior to their own. During training, which is an iterative process, Watson and MSK oncologists assess possible treatments for each case, scoring each one green (recommended), yellow (for consideration), or red (not recommended). The team hopes for overall agreement, and dreads "red-green" disagreement. Most common is a "yellow-green" disagreement. While human judgment still makes the better choice most of the time, Seidman says, “Sometimes we realize, 'Watson got that one right and we got it wrong.'"

Even with advancements in technology, the prospect of artificial intelligence treating patients with cancer still remains out of reach. At least, for now.

IBM's Watson has Potential Partnership With Oncologists

Extra vigilance, careful management, and an emphasis on empathy makes treating cancer pain more effective during an opioid addiction epidemic, Judith A. Paice, PhD, RN, discussed during a presentation at the 2017 Lynn Sage Breast Cancer Symposium. 

Both patients and physicians now approach opioid use with extra caution that is understandable in the current climate, but their caution may be excessive in some cases, said Paice, director of the Cancer Pain Program and a research professor of medicine at Northwestern University's Feinberg School of Medicine, as well as a past president of the American Pain Society.

More patients than ever are living with pain. As of 2012, there were 32.6 million people worldwide living with cancer and that number is expected to jump to 52.2 million by 2030, according to the International Agency for Research on Cancer.

Improvements in cancer treatment have led to millions of patients surviving for a decade or more, with a corresponding increase in the number who live with pain. Paice cited a review in the journal Pain estimating that 40% of cancer survivors live with some degree of pain, and 5% to 10% have severe chronic pain that limits their ability to function.

 One in 5 childhood cancer survivors report pain.

Amid the hype concerning overuse of opioids, Paice is concerned that some patients still remain undertreated due to addiction fears that do not match the evidence. "After Prince died, people asked me to take them off their fentanyl patches, and I had to reassure them that Prince hadn't died from a fentanyl patch," she said. Though long-term opioid addiction often begins with the use of prescription painkillers like oxycodone, Paice cited research showing that 3 out of 4 such addicts acquired those pills illicitly rather than through a legitimate prescription.

Paice said both primary care physicians and insurance companies sometimes treat last year's CDC guidelines for opioid treatment as a mandate,

 even though they may be too conservative to be applied to cancer-related pain. "Many of us protested the recommendation that patients be given no more than 50 mg of morphine and only a 3-day supply at discharge," she said. "Imagine that 80-year-old woman who lives far from the hospital, relies on family members, is discharged on a Thursday, and now on a Saturday or Sunday has to get a new prescription."

Paice also cited statistics showing that while there is a rough correlation between sales of prescription opioids and deaths from opioid overdose, the number of deaths specifically from prescription opioids has plateaued (though deaths from illicit opioids are still climbing).

Nonetheless, the addiction danger is real and there are possible long-term health complications from sustained opioid use, even when the patient is not an addict, Paice said. "We didn't see these effects when I was starting out in practice because we only prescribed opioids at the end of life." They include constipation, mental clouding, upper gastrointestinal symptoms, various endocrinopathies, sleep apnea, and a poorly understood risk of opioid-induced hyperalgesia. There is even some evidence suggesting that prolonged opioid use hinders healing and may increase risk of cancer recurrence.

Paice recommended the following measures when giving cancer patients the full benefit of opioid pain relief in order to minimize risks:

Assess the patient's potential for addiction. Do they smoke, drink, use other drugs, or gamble? Have they done so in the past? Do any of their biologically close relatives demonstrate addictive behavior? Have they been sexually abused (a strong risk factor for addiction)? Do they worry about becoming addicted?

Do a urine tox screen at least annually for each patient on opioids, and more frequently for those at a higher risk of addiction, to assess whether they are overusing their pain medication or abusing other substances. Use your state's prescription drug management program, available in all states, except Missouri, to check whether your patients are getting multiple opioid prescriptions filled at the same time. (Paice discovered 1 patient was getting hydrocodone from both her and an orthopedic surgeon, from 2 different pharmacies.)

It's important to make sure patients are using their opioids for pain, rather than to relieve anxiety or help them sleep. "It's acceptable to take your medication before bed if you have vertebral fractures," and know that you'll have pain when you lie down, Paice said. "But if you're taking it every night at 9 to make you sleepy, we have a problem."

 Illicit users of prescription opioids get their drugs from legitimate users, so patients need to be on guard. If patients come up short on their pills, they may be taking too many—or maybe someone is stealing them, Paice said. "I tell patients, 'Maybe it's not your grandkids, but it's their friends.'" Patients who have pills they no longer need should dispose of them through a formal drug take-back program.

All cancers (excluding non-melanoma skin cancer) estimated incidence, mortality and prevalence worldwide in 2012. International Agency for Research on Cancer website. http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx. Accessed September 14, 2017.

Heathcote LC, Eccleston C. Pain and cancer survival: a cognitive-affective model of symptom appraisal and the uncertain threat of disease recurrence. Pain. 2017;158(7):1187-1191. doi: 10.1097/j.pain. 0000000000000872.

Dowell D, Haegerich TM, Chou R. CDC guideline for prescribing opioids for chronic pain — United States, 2016. JAMA. 2016;315(15):1624-1645. doi: 10.1001/jama.2016.1464.

Extra vigilance, careful management, and an emphasis on empathy makes treating cancer pain more effective during an opioid addiction epidemic.

"Opioid Epidemic" Increases Challenge of Treating Cancer Pain

Despite the unprecedented polarization of the nation's views on what's wrong with the healthcare system, both sides think doctors should fix it.

"If there's one thing Democrats and Republicans agree on, it's that we have to move to value-based care," said Robert Laszewski, president of Health Policy and Strategy Associates and a former insurance industry executive who now consults on the business and politics of healthcare. "Both sides count on it, because they won't have to take away anyone's benefits if 

In his keynote address at the Large Urology Group Practice Association, Laszewski, a frequent speaker at LUGPA gatherings, delineated the current political and business landscape for physicians, and urged his audience to band together and create an offensive strategy.

"You need to get organized, because the guys who are paying you are getting organized," Laszewski said, citing the proposed mergers of already giant insurance companies, Aetna with Humana and Anthem with Cigna.

Even if those mergers fail to receive government approval because of well-founded antitrust concerns, the health insurance market is already highly consolidated and powerful. United HealthCare, the nation's largest single insurer, has annual revenues of more than $130 billion, and Laszewski noted that Blue Cross/Blue Shield would outstrip that figure if all their revenues were combined.

"You're caught in the middle, whatever happens."  

Physicians shouldn't look to the government to help. The Centers for Medicare and Medicaid Services are also moving quickly to value-based reimbursement. The Obama administration has set a goal of tying half of Medicare spending to performance by 2018, even though the costs associated with accountable care organizations have been higher than projected. 

In 2019 physicians are scheduled to face a fork in the road with Medicare: either stick with the fee-for-service model and face a host of existing and new requirements under the Merit-based Incentive Payment System (MIPS), or move to an Alternative Payment Model (APM) that is based on providers assuming substantial financial risk for outcomes but also confers a 5% lump-sum bonus on physicians’ Medicare payments for 5 years, followed by a 0.75% increase in payments each year thereafter.

"You have the choice of being in the fee-for-service system where they'll treat you like 5-year olds and beat the hell out of you every day, or you can go into the adult system, make 5% more, and manage your own future," Laszewski said. In a moment of preaching to the choir, he added that a physician's best strategy in the new environment is to join a large group practice that has the resources to succeed in a value-based environment.

Five years after passage, the Affordable Care Act is working in some ways but failing in others, Laszewski said. On the plus side, millions more people are insured, either through purchasing insurance or by the expansion of Medicaid (now extended in 30 states, though most of the Republican south is still holding out). The extension of insurance coverage means more patients are able to pay their bills.

On the minus side, enrollments of eligible members of the middle class are lagging. Once they no longer qualify for significant subsidies, they can't afford the high premiums and deductibles for plans on the government exchanges. That leaves the exchanges predominantly to enrollees on the low end of the income spectrum, and also tilts enrollment heavily toward those with chronic conditions like congestive heart failure and diabetes, who benefit most immediately from being insured.

"The shrewdest politician on healthcare is Hillary [Clinton]," Laszewski said. "She zeroes in on out-of-pocket costs being too high, and responds directly to that." Clinton is also taking a populist and popular line on drug prices, advocating for letting Medicare negotiate prices directly with drug companies, and allowing Americans to import drugs from Canada.

Laszewski called a repeal of Obamacare politically impossible, even though most Republican candidates have made repeal a centerpiece of their campaigns.  Even if the Republicans win the White House and hold the Senate, he predicts they will never get the 60 votes they need in the Senate for repeal.

Moreover, the Republicans' counterproposals for fixing the system, which include repealing the Medicaid expansion ("Good luck with that," Laszewski said) and reinstating preexisting condition restrictions for anyone who hasn't been continuously insured for 18 months, may make them popular with their own party but torpedo their chances in the general election.

"I think Republicans need to be more willing to fix Obamacare, rather than trying to replace it with something just as problematic," Laszewski said.

Healthcare is going to occupy an increasing share of the federal budget in the next 40 years, and Laszewski said physicians will start feeling the squeeze soon, as the combination of healthcare and interest on the national debt propels the government's total obligations significantly above its revenue.  

"We're going to be doing a lot more with a lot less money in years to come."

View more from the 2015 LUGPA Annual Meeting

The keynote address at the 2015 LUGPA Annual Meeting urged physicians to band together and create an offensive strategy when it comes to the nation's healthcare system.

Physicians on the Offense: Get Organized to Thrive in This Payment Arena

Hormone therapies for prostate cancer aimed at reducing serum androgens are trained on the wrong target: the testes and the adrenal glands. Rather, they should attack the prostate cancer cells themselves, said Adam Kibel, MD, at the 2015 LUGPA Annual Meeting.

“We are very good at driving serum testosterone down to nothing, but it hasn't translated to an improvement in overall survival,” said Kibel, who is chief of Urology in the division of urologic surgery at Brigham and Women's Hospital.

“We have thought that if we kill enough cells, the few that are left will die as well, and maybe that's true, but not by attacking at the level of the blood. Prostate cancer cells make their own androgens, and that's where we need to achieve castrate levels.”

He cited a 2008 study showing that metastatic tissues after chemical or surgical castration had up to four times the amount of testosterone as normal cells.

“We should be doing this, because we understand the disease, we see these patients, and we're not just surgeons,” Kibel said. “We were giving them medications to control their BPH before we diagnosed them with cancer.”

Kibel described in detail the use of two specific agents: the steroidal antiandrogen abiraterone acetate (Zytiga), and the nonsteroidal antiandrogen enzalutamide (Xtandi).

Cancer cells can elude many androgen deprivation strategies in several ways: by making their own testosterone; by increasing their numbers of androgen receptors to take advantage of the few androgens still available at castrate levels; and by mutating to take advantage of other types of steroids. “The cancer cell figures out how to beat a drug, and regrows, and the next thing we know we're fighting more aggressive cells,” Kibel said.

Abiraterone works by blocking testosterone production within the cell, and was approved by the FDA in an expedited review in 2011 because when taken with prednisone it improved overall survival rates compared with prednisone alone. The trial was stopped early because the improvement was so significant. Patients on the combination regimen survived progression-free for 16.5 months compared with only 8.3 months for those on prednisone alone, and the latter group survived an average of 27.2 months in all. The study was stopped before obtaining an average survival rate on the group receiving abiraterone.

In two separate trials, the drug showed good results both with patients who had previously received chemotherapy with docetaxel and those who had not.

The “nuts and bolts” of administering abiraterone include:

·  Take on an empty stomach: no food for 2 hours before or 1 hour after

·  Swallow the (very large) tablets whole

·  Monitor patients for hypertension, hypokalemia, liver toxicity, and fluid retention.

Liver function tests should be done every 2 weeks for the first 3 months, and monthly thereafter. If the tests show toxicity, the manufacturer recommends stopping the drug and then starting again at a lower dose, but Kibel advised attendees to consider bringing in a medical oncologist instead. He also recommended having a specific person in the practice responsible for prescribing and monitoring these drugs, if the practice doesn't already have an oncologist.

Abiraterone can have significant interactions with several drugs, including phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, and phenobarbital. Kibel noted that abiraterone can increase the level of some drugs, including the common cough suppressant dextromethorphan.

Enzalutamide works by blocking androgen receptors, and blocks them almost as well as dihydrotestosterone itself, Kibel said. It inhibits the binding of androgens to the receptors, as well as nuclear translocation of androgen receptors to the cell nucleus and association of the androgen receptors with DNA. A trial of enzalutamide versus placebo in patients who had previously had chemotherapy with docetaxel showed a median survival rate of about 5 extra months. A similar trial is in progress for patients who have not had chemotherapy.

Enzalutamide may be taken on either an empty or a full stomach, but must also be swallowed whole. Blood pressure and CBC should be monitored, and patients should be told to contact their physician if they experience seizure, headache, lethargy, confusion, or blindness—all symptoms of a rare side effect called Posterior Reversible Encephalopathy Syndrome. "I've never seen this side effect, but it looks like it progresses really fast," Kibel said. Fatigue, the most common side effect noted in the trial, is also likely to show up in office practice, he added. "I've been staggered by how much fatigue I've seen."

Enzalutamide reduces the plasma level of several types of medications, including fentanyl, warfarin, phenytoin, and omeprazole.

For both abiraterone and enzalutamide, men should wear a condom during any sexual activity if pregnancy is a concern, since either drug could pass to his partner and is contraindicated for pregnant women.

Hormone therapies for prostate cancer aimed at reducing serum androgens are trained on the wrong target: the testes and the adrenal glands. Rather, they should attack the prostate cancer cells themselves.

Deliver Androgen Blockade at Prostate Cancer Cells to Achieve Castrate Levels

Patients treated with hormone-based therapies for androgen-sensitive prostate cancer have better outcomes when they achieve testosterone levels <7 ng/dL—significantly lower than the 50 ng/dL that the FDA recognizes as a castration threshold, E. David Crawford, MD, said in a presentation at the 2015 Large Urology Group Practice Association (LUGPA) Annual Meeting.

“Prostate cancer is a hormonally dependent cancer and we need to understand that. The goal is to lower or block androgens, and the lower the better. Get the level as low as you can and keep it as low as possible,” said Crawford, who is head of Urologic Oncology at the University of Colorado. He cited studies showing a two-fold difference in risk of death between patients with testosterone levels<20 ng/dL and those with levels >50 ng/dL.

According to Crawford, the FDA still bases its standard on an old technique for measuring testosterone that cannot detect levels much lower than 50 ng/dL. Newer chemoluminescent and mass spectrometry techniques can measure as little as 0.1 ng/dL. Now that patients can be tested for such low levels of androgens, Crawford said mounting evidence supports a standard of <20 ng/dL.

The FDA also seems to apply a different standard to hormone therapies for prostate cancer than to other types of drugs, Crawford observed. “These drugs are letting us down,” he said. “Less than half the time do you keep testosterone in a range less than 20, and a quarter of the time it’s above 50. That would not fly with the FDA if it were some other kind of drug with that variation."

When the LHRH agonist leuprolide was approved for prostate cancer treatment in 1985, it was based on a single study comparing the drug with DES in a group with a total of 199 patients, and measuring survival rates at 1 year. “That would never ever happen today,” Crawford said.

The session at LUGPA examined and compared the abundance of current approaches to androgen deprivation, including estrogens (eg, diethylstilbestrol), bilateral orchiectomy, LHRH agonists (eg, leuprolide), and the GnRH antagonist degarelix (Firmagon). Crawford also discussed antiandrogens, such as flutamide and bicalutamide.

“If we had an antiandrogen that really worked, I do believe it would be the best way to treat,” he said.  However, he cited a study showing that bicalutamide is less effective than bilateral orchiectomy for preventing the progression of cancer. The drug also has gynecomastia as a significant side effect.

Crawford added that the newer antiandrogen enzalutamide (Xtandi), approved by the FDA in 2012, has shown a survival advantage of almost 5 months over placebo when used after chemotherapy.

Bilateral orchiectomy has historically been considered the "gold standard" for starving prostate tumors of androgens, because it is a relatively quick and inexpensive outpatient procedure and it reduces testosterone more quickly than any drug can.

But Crawford disputes the assessment. Orchiectomy is extremely unpopular with patients. He observed that in one study, almost 90% choose an injection of LHRH agonist rather than the irreversible surgery, and he speculated that most meeting attendees probably have not done an orchiectomy in at least 6 months.

The procedure also has a broad spectrum of side effects, including negative sexual and vasomotor effects, metabolic and cardiovascular implications, and bone loss. It also does not eliminate all androgens, since some are produced by the adrenal glands and by the prostate tumor cells themselves, and these small amounts can be enough to support the continued growth of the cancer.

He cited one study showing that tissue concentrations of dihydrotestosterone after orchiectomy are 2 ng/g—lower than the levels of 5 ng/g for both BPH and cancer, but not that much lower than a normal level of 2.5 ng/g.

Most importantly, orchiectomy causes an increase in follicle-stimulating hormone (FSH), which in itself may play a role in cancer progression, as well as causing cardiovascular problems.  Several studies by Crawford and others have shown that FSH stimulates the growth of prostate cancer cells in vitro.

The different pharmacological approaches to ADT are by no means equal in their ability to block androgen production, and their performance can be erratic, Crawford said. A 2007 study showed that one in four patients treated with LHRH agonists had testosterone levels >50 ng/dL during their therapy. Other common variations include testosterone surges or flares. And some patients don't respond at all.

Crawford urged attendees to monitor patients’ testosterone levels regularly while they are receiving LHRH agonists and be alert for inadequate response, because the performance of secondary therapies like steroids and antiandrogens may depend partly on how well the initial therapy works.

“When patients fail hormonal therapy, second-line therapy gives us a 30% response, and why is that?" he asked. “It's because they weren't suppressed to begin with, and if we did a better job of doing that, that wouldn't happen."

E. David Crawford, MD, discussed issues with FDA standards for ADT agents and current treatment approaches to androgen deprivation in prostate cancer at the 2015 LUGPA Annual Meeting. 

Elizabeth Gardner