Since its approval in 1998 to treat metastatic breast cancer, the anti-HER2 monoclonal antibody trastuzumab has dramatically expanded life expectancy and improved quality of life for women diagnosed with HER2-positive disease. It remains the standard-of-care, first-line treatment for metastatic breast cancer. In less than a decade, the FDA has added three new drugs to the arsenal to treat advanced HER2-positive disease, while a growing number of clinical studies are evaluating dual-agent approaches to therapy through a variety of drug combinations.

At the MBCC mini-symposium, Kimberly L. Blackwell, MD, the director of the Breast Cancer Program at Duke Cancer Institute, discussed current treatment options in a presentation entitled “Targeting HER2 in Metastatic Breast Cancer in 2014.” She put emerging treatment trends into context during an interview in advance of her talk.

How have treatment options and prognoses changed over the past decade for women diagnosed with HER2-positive breast cancer?

We can no longer speak of diagnosing breast cancer in broad terms, but rather of different subtypes of breast cancer and cancer stage. Prognoses, based on a specific cancer’s biology, are very different. But we can say that the prospects for women diagnosed with HER2-positive breast cancer have improved. With certain subtypes, discovered in the early stages of the disease, we can start talking about a cure. This marks a paradigm change; we could not have said this 10 years ago. There are now people with HER2-positive disease who have no recurrence if they are treated earlystage with trastuzumab. The prognosis for these women is pretty tremendous, and it has allowed us to save years and years of life for them.

How have prospects changed for women with HER2- positive metastatic disease?

There are a lot of options for these women if their cancer remains HER2-dependent. We now treat metastatic breast cancer as we would a chronic disease, such as diabetes or heart disease, with targeted therapies and combinations of therapies.

A serious challenge we face with some of these women, however, is brain metastases. This is a tragic situation, especially for women who have lived a high-quality life for several years and then develop metastases. It is a difficult cancer to treat, and these patients may also suffer the long-term effects of stroke. We must recognize that we aren’t able to adequately treat progressive brain metastasis.

Where are the post-trastuzumab drugs proving most effective, and in what settings?

The approval of T-DM1, an antibody-drug conjugate, is changing the way we care for metastatic breast cancer and solid tumors in general. Treatment that doesn’t hurt the immune system is a major breakthrough that will improve patient care. Lapatinib is not super effective therapeutically. We see that lapatinib and trastuzumab are more effective together than lapatinib alone. But there may be new life for this drug. The data we have now do not look at combinations with T-DM1 or the effect of layering trastuzumab with lapatinib or pertuzumab.

What role are dual-agent therapies playing in the treatment of metastatic disease?

We’re doubling down on HER2-positive cancer. There will be few studies from now on that evaluate trastuzumab alone; in metastatic breast cancer, dual agents are here. The dilemma facing clinicians over the next 5 years is going to be sequencing.

How do the newer drugs improve upon the performance of trastuzumab?

There is a limited ability to improve upon trastuzumab’s performance with these newer drugs. There are studies whose results we’re anxiously awaiting, but it’s really unclear how useful they will be. With healthcare reform and the cost to society of developing and prescribing new drugs, we need to look very carefully at the value of small incremental gains and to ask some very hard questions as a society: Is it worthwhile to add new medications? How many people need these new expensive therapies?

Are there drugs on the horizon that may improve treatment for HER2-positive disease?

Everolimus [approved in HER2-negative settings] may prove valuable. While it showed only a small improvement in progression-free survival in BOLERO-3 (1.2 months), I don’t dismiss it. I think its capacity to cross the blood-brain barrier is important and it may prove useful in addressing brain metastases. I think we will also see neratinib come to the table. We saw in the I-SPY 2 study of neratinib in the neoadjuvant setting that it met its primary endpoint. I think that studies of PI3-kinase inhibitors are also going to yield some interesting results.

This is the therapeutic area I’m most excited about now. If trastuzumab can make such a difference and it’s a monoclonal antibody, we can only imagine what a polyclonal response would be like. A proven vaccine in the HER2-positive sphere would have a huge impact. The obstacle to a vaccine is that it’s hard to develop. We would also need to figure out which patients are capable of mounting an immune response, which aren’t, and then determine how to screen for that.

Which clinical studies stand to have the largest impact on the direction of treatment?

In metastatic disease, we are waiting for full results from MARIANNE, which for the first time evaluates whether T-DM1 alone or combined with pertuzumab is better than trastuzumab and a taxane. This could [establish T-DM1] as a first-line therapy in metastatic disease, and so MARIANNE is a game-changing study. The APHINITY trial, [which compares trastuzumab plus chemotherapy with and without pertuzumab as adjuvant therapy for primary breast cancer] will also be important. A question for clinicians going forward will be whether to choose pertuzumab or lapatinib in the adjuvant setting. This will be a dilemma, and the answer will be driven by patient-reported outcomes.

How effectively are we diagnosing and treating molecular subtypes of breast cancer?

We now have the capability to look at 50 genes linked with breast cancer. What’s missing is not the ability to accurately characterize cancers through diagnostic testing, but the infrastructure that allows practicing doctors to do this and then select appropriate treatments for their patients based on it. We need to have a transparent dialogue about what’s holding up getting this capability to the clinic, and then to forge a commercial/academic partnership to get it done. It will be important to develop an assay that we can all use regularly, and I believe there should be financial incentives to deliver this assay. I use the Oncotype DX test because I feel it helps me take better care of my patients.

Concerning the need for biopsies, my least favorite word is “optional”:âŽ¯It makes the choice sound unimportant. It’s essential to know what sort of tumor a patient has. We do not want to be in the position of telling a patient that we didn’t have the impact we’d hope to have on her cancer because we didn’t know what it was. If I tell a patient I want to know what’s driving her tumor forward, she will almost always agree to a biopsy. They do have a cost, but treating a patient with a drug that won’t help them is also costly. This applies to clinical trials as well. We have no ability to say which subsets of patients benefit from a medication if we don’t collect tumor biopsies and figure it out.

View more from the 2014 Miami Breast Cancer Conference

Articles

Since its approval in 1998 to treat metastatic breast cancer, the anti-HER2 monoclonal antibody trastuzumab has dramatically expanded life expectancy and improved quality of life for women diagnosed with HER2-positive disease.

Blackwell Explores Emerging Trends in Treating HER2 Metastatic Breast Cancer

		Robert K. Royce Distinguished Professor

		Washington University School of Medicine

Two years after the FDA denied a request to expand the indication of finasteride and other 5α-reductase inhibitors to prevent prostate cancer, a major study has cast doubt on the concerns that prompted the denial: that the drug raised the risk of more lethal cancers. Results from an 18-year follow-up study

 of the National Cancer Institute’s landmark Prostate Cancer Prevention Trial (PCPT), which evaluated the drug’s safety and efficacy, found a slightly higher rate of high-grade cancers among the men taking finasteride but no difference in survival rates between treated men and those in the placebo arm, even among men with a high-grade cancer diagnosis (

The analysis showed that finasteride reduced the risk of low-grade prostate cancer by about one-third. Yet, the drug has seen little use in cancer prevention since the initial report, published in 2003, which found that it reduced the risk of prostate cancer by about 25%, but increased the risk of high-grade cancer by about the same amount. Those findings sparked debate over whether the drug caused more serious cancers or made it easier to detect them. In the latest analysis, Thompson et al collected data on the incidence of prostate cancer among PCPT participants and then searched the Social Security Death Index to assess survival status through October 2011.

Although this follow-up study may have allayed some concerns about finasteride, it remains unclear whether clinicians will now use the drug as a cancer prevention tool. Proponents of cancer prevention with finasteride and other 5α-reductase inhibitors are reassured by these findings but other considerations, such as the reduced emphasis on prostate-specific antigen (PSA) screening and the need for clinicians to use PSA differently in men receiving these agents, may result in little change in the use of these medications. These drugs remain approved and widely prescribed as treatments for benign prostatic enlargement, however, and use for that indication may well rise.

For more than a decade, Gerald L. Andriole Jr, MD, of Barnes-Jewish Hospital and the Siteman Cancer Center, has been conducting research into the optimal use of finasteride and other 5α-reductase inhibitors. In this interview with OncologyLive, Andriole discusses the implications of the latest finasteride findings.

OncologyLive: Does finasteride have a role in cancer prevention going forward?

 I think it does, and I think it should be used selectively for this purpose. If a man is going to be screened with PSA, I think that 5α-reductase inhibitors will improve the overall effectiveness of screening for two reasons: They reduce the diagnosis of low-grade cancers that do not warrant treatment and they improve the ability of PSA to detect more aggressive cancer. Reducing the diagnosis of trivial cancers is important, as a major problem with screening is overtreatment of lowgrade cancers. This causes real harm to patients as they may experience side effects from treatment while getting no benefit from it.

Finasteride also makes PSA a better marker for aggressive cancers. For men taking [finasteride], PSA initially falls. If PSA subsequently rises above the nadir, then that is a strong signal that an aggressive cancer may be developing. The interpretation of PSA is different for men taking this drug. While urologists are sensitized to these nuances, many primary care providers and family doctors may not know that a rising PSA for men receiving finasteride, even if it is still under 4, is not normal and is a serious warning sign that an aggressive cancer may be developing. The potential for misinterpretation of PSA in this way was one of the reasons the FDA decided not to modify the label.

How should clinicians interpret the updated results of the PCPT?

Individuals who were concerned that finasteride use promoted aggressive prostate cancer should find reassurance from this analysis. The results show that the drug is safe if patients are closely monitored and PSA is interpreted correctly. But will that message get out to primary care physicians? I doubt it. Will they prescribe it for prostate cancer prevention? Probably not. It’s a complicated issue in which they hear that experts disagree, and there is a movement against widespread PSA screening at the moment anyway. This drug is most beneficial for men at higher risk of prostate cancer who should be getting screened. On the other hand, use of this drug for men with benign prostatic hyperplasia [BPH] could well increase.

How has finasteride’s use evolved over time?

Medical missionaries including students working in Haiti and the Dominican Republic in the 1970s identified villagers with disorders of sexual differentiation, including small testicles and no BPH. These men were born with a deficiency of the enzyme 5α reductase. Learning this, the academic and pharmaceutical communities realized they could potentially eliminate the development of BPH by inhibiting this enzyme with drugs. Two such agents have been approved: finasteride and a related drug, dutasteride, a dual 5α-reductase inhibitor. These drugs were initially approved for treatment of men with BPH. Later, as results of the PCPT trial and the REDUCE trial became known, there was hope they would be approved for prostate cancer prevention as well. For this use, the men who stand to benefit most from receiving these drugs are those at high risk of aggressive cancers, including men with a strong family history of prostate cancer and African-American men. Other tools, such as measurement of PSA at an early age—in the 40s for example&mdash;may also identify at a relatively young age which men are a high risk of prostate cancer.

What is the drug’s mechanism of action?

Finasteride inhibits the enzyme 5α reductase, which converts testosterone to dihydrotestosterone (DHT). DHT is a very potent hormone that causes the prostate and prostate cancers to grow. By reducing DHT, finasteride and dutasteride slow the growth of many prostate cancers and cause many prostate cancers to actually shrink in size.

Is it clear whether finasteride enhances detection of prostate cancer—particularly high-grade cancer&mdash; or causes it?

I think finasteride enhances detection of prostate cancer for two reasons. First, it makes PSA a better marker and second, it shrinks the prostate by approximately 25%, thereby making biopsies more accurate. A standard prostate biopsy consists of 12 cores, and the smaller the prostate the more complete is the assessment of whether cancer is present. In larger prostates, the cores can be so widely spaced that cancers are missed by the biopsy.

What are the principal adverse effects of finasteride?

There are sexual side effects, including higher rates of erectile dysfunction and reduced semen volume. I discuss this with my patients. I tell them that not everyone develops these side effects, but we will stop the medication if they do. These effects are usually not permanent.

Are there broader concerns about the entire class of 5α-reductase inhibitors?

I don’t think so. In the PCPT, 18,000 patients were randomized over the trial’s two arms and now have been followed for close to two decades. An even larger number of patients were studied in a Swedish analysis

 that assessed 5α-reductase inhibitor use in men with BPH. It found a decreased risk of lower grade cancers and no increase in the risk of higher grade cancers. Finally, a third trial, the REDUCE study

 of dutasteride, for which I was the principal investigator, confirmed the safety and efficacy of dutasteride for chemoprevention of prostate cancer in men at high risk. In the aggregate, these three studies, plus over 20 years of experience in using these drugs for men with BPH, are very reassuring.

How should we approach prostate cancer prevention?

We now have three major studies—REDUCE, PCPT, and the Swedish study&mdash;that evaluate the efficacy of cancer prevention. As data from these studies become more widely known, additional data come out, and the medical community comes to a consensus on the need for PSA screening, there will be more clarity and willingness to use these drugs for prevention.

Are we closer to finding a balance between intrusive and potentially harmful screening and successful early intervention?

I think the guidelines of multiple professional organizations are starting to reflect that. Doctors are becoming more aware of the nuances of prostate cancer detection and the consequences of overtreatment. We are also finding new biomarkers in addition to PSA that will help minimize detection and treatment of minimal cancers. Studies on these new biomarkers will be released soon.

		Figure. Prostate Cancer Incidence in PCPT Trial After 18 Years

		PCPT indicates Prostate Cancer Prevention Trial. Thompson IM et al. 

			Thompson IM, Goodman PJ, Tangen CM, et al. Long-term survival of participants in the Prostate Cancer Prevention Trial. 2013; 

			Grubb RL, Andriole GL, Somerville MC, et al. The REDUCE Follow-Up Study: low rate of new prostate cancer diagnoses observed during a 2-year, observational, followup study of men who participated in the REDUCE trial [published online ahead of print September 25, 2012]. 

			Robinson D, Garmo H, Bill-Axelson A, et al. Use of 5α-reductase inhibitors for lower urinary tract symptoms and risk of prostate cancer in Swedish men: nationwide, population based case-control study. 

Two years after the FDA denied a request to expand the indication of finasteride and other 5Î±-reductase inhibitors to prevent prostate cancer, a major study has cast doubt on the concerns that prompted the denial: that the drug raised the risk of more lethal cancers.

PCPT Trial Helps Confirm Role of 5Î±-Reductase Inhibitors in Prostate Cancer Prevention

	As politicians on Capitol Hill pursue divergent visions for the country’s fractured healthcare system, a growing number of physicians, hospitals, and payers are quietly joining forces to explore new models to meet such shared challenges as rising medical costs and declining reimbursements.

	In one notable collaboration, Advanced Medical Specialties, a multisite oncology practice in the Miami-Dade—region Florida Blue, the state’s largest private insurer, and Baptist Health South Florida, the hospital group, are forming a cancer-specific accountable care organization (ACO) that the partners contend will streamline the delivery of care, rein in costs, and improve outcomes.

	ACOs aim to improve quality and efficiency by integrating clinical services and communications across practice areas, implementing evidence-based treatments, and keeping close track of care and outcomes through shared electronic medical record systems, among other measures. While conceived as a model for primary care, they are gaining attention in specialty areas such as oncology, where care is especially complex, management-intensive, and expensive.

	“We have been seeing rapidly escalating oncology costs in a state with a high incidence of cancer. We are exploring ways to work collaboratively to build an integrated system where high-quality care provided to members will lead to more efficient care. In the end, this reduces the cost of care,” said Jonathan Gavras, MD, senior vice president of delivery systems and chief medical officer for Florida Blue.

	Under the new organization, physicians will act as primary navigators who are accountable for patient care, while guiding patients through the healthcare system. When patients enter the hospital, they will retain “strong connectivity” with the physician group, Gavras said, through continuity of care, adherence to clinical pathways, and the use of electronic medical records. The healthcare plan will then aggregate information on the care provided and share those results with the hospital and physician partners. As they seek to contain costs, they will look closely, for example, at avoided emergency room visits.

	The partners are instituting a shared-savings program they say will act as an incentive to reduce unnecessary services. In setting it up, they began by identifying a population of patients with common cancers, including leukemia, lymphoma, and breast, gastrointestinal, prostate, gynecologic, and thoracic cancers, and then examined the care they were provided over the course of a year and tabulated its cost.

	“We looked historically at the cost of care for this population, and then set a budget per patient, per condition going forward for a year,” said Leonard Kalman, MD, chairman of Advanced Medical Specialties. “We’ll see if we can beat that budget, and if we do, the savings would be split. We’re still in the midst of looking at where dollars have been spent and identifying those areas where we think the cost curve can bend.”

	In seeking efficiencies, Kalman said that his practice has focused on evidence-based treatment regimens, advance care planning for end-of-life care, and lowering the number of unnecessary hospital admissions, as well as emergency room visits. The practice employs “chemotherapy educators,” for example, to meet with patients before they receive their first course of chemotherapy as a way of reducing emergency room visits and admissions related to side effects.

	“Avoidable admissions are a top priority. We may need to create a lower-intensity triage area, possibly within our infusion suites, so patients don’t have to go to the hospital,” he said, noting that while these services are presently set up for weekday, daytime hours, the partners are exploring ways to avoid emergency room visits and admissions at night and over the weekend.

	Access to electronic records, via secure networks over the Internet, will reduce medical errors and ensure that providers are not repeating diagnostic tests, Kalman said, adding that the group is currently working out privacy issues and logistics as it sets up the new system.

	“We also need to encourage patients to consider advance care planning, working with doctors and nurse practitioners. This would include avoiding the use of chemotherapy, ICU, hospital or emergency room admissions for the last 30 days of life,” he said, noting, however, that both the health plan and the hospital system will need to “market” advance care planning if it is to be successful.

	The cost of drugs continues to pose a challenge that is not easily tackled, the partners said. “Drug prices are significantly rising due to new drugs entering the market. They’re expensive, but they are positive clinical advances. What we can do is make sure they’re used appropriately, under the right conditions, and in the right dosages,” Gavras said.

	Kalman explained that for doctors, the new system would provide a way to “to move away from some of the old ways of getting paid, such as on drug margins,” where reimbursements have been declining and where, “following evidence-based care at a high level of compliance, there is little if anything left to save.”

	“Our practice has been dealing in a positive way with Florida Blue, and we realized that we should work with them to try to find a new way to get paid. This is a good first step,” he said. “You start overcoming historic distrust and barriers, and that’s invaluable.”

	Kalman said that his practice and the hospital will continue to charge on a fee-for-service basis, but would consider replacing it with another payment method after the system is fully up and running in the next 2 to 4 years.

	While the payment model does not put a dollar value on services such as the coordination of care or patient education, or reimburse providers for them, it does reward them for the efficiencies and cost reductions that come from implementing them, Gavras said.

	“It’s a different way of financing healthcare. It’s margin-based reimbursement versus revenue-based. The better I do, the bigger piece of the savings I keep, once hitting quality metrics,” he said, while declining to discuss how the shared savings would be distributed, other than to say that the formula had been worked out “to the satisfaction of the three parties.”

	The partners said that patients struggling with rising copays will also benefit from the new system, which is designed to reduce medical complications and errors and lower their out-of-pocket costs by eliminating duplicated and unnecessary services.

	Although patients will still see the same doctor, they will take part in an enhanced system where there is significant coordination of care. Quality parameters will be ensured through the use of evidence-based pathways and Quality Oncology Practice Initiative (QOPI) certification. While the first focus is clinical outcomes, Gavras said, the group plans to eventually measure patient satisfaction via surveys.

	He said that employers must agree to participate, noting, “Employers, too, need to understand that this is a different way of paying doctors. Large employers seem prepared to accept this. They should see savings if the program is effective.”

	The most important thing was getting the leadership aligned. We all put our cards on the table—our financial data&mdash;and shared data that never would have been shared before.”

	To Gavras, data analysis, “the aggregation and analysis of costs and clinical condition and financial analysis,” is the group’s major investment so far. But before the partners could even begin to look closely at costs, they had to achieve a more significant milestone, he said. “The most important thing was getting the leadership aligned. We all put our cards on the table—our financial data&mdash;and shared data that never would have been shared before.”

	The senior leadership of each organization then spent months “actively involved and engaged in the strategy setting of the oncology ACO,” said Ralph Lawson, corporate executive vice president and chief financial officer for Baptist Health South Florida. He added that staff members of the respective teams serve as project managers and hold weekly meetings to review data and maintain adherence to timeframes and initiatives.

	“For the immediate future, participants must rely primarily on the breadth of data available from the payer to attribute patient population and to guide decision making related to clinical and operational improvement opportunities,” Lawson said. “At Baptist Health, we are in the process of evaluating these aforementioned opportunities, and, if necessary, we will make decisions related to the appropriate staffing mix/complement, as well as department structure, to support the ACO collaborative.”

	Kalman called the build-out time a “2- to 4-year proposition.” He explained, “We finished the contracting stage. We are now delineating the care processes that need to be instituted or tweaked or enhanced, such as a triage system, advance care planning, chemotherapy education, and continued adherence to pathways and QOPI. Then we sit back and measure and readjust the care processes, and indeed perhaps the contract, as data is accrued,” he said. “After that, might we be willing to accept a ‘bundled payment’ with the hospital? We will see. The end game is accepting risk, but we need to get all this experience under our belt.”

 The Patient Protection and Affordable Care Act directed the Centers for Medicare & Medicaid Services to create a mechanism by this year for sharing cost savings with ACOs—which it defines as provider groups that assume responsibility for the full spectrum of care for sizeable, defined patient populations&mdash; if they meet quality targets and can document cost reductions for their Medicare patients.

	Gavras said that Florida Blue began working on the new model well before the healthcare reform law was passed. “This was going to happen no matter what. With changes in the cost of drugs and a higher incidence of diseases like diabetes and cancer, the current system is not sustainable,” he said, adding that the insurer plans to expand this model to its Medicare Advantage members within the next few months.

	Lawson said that he viewed the industry’s transition from volume-based reimbursement models to value-based models “inevitable and required.” He said, “Simply put, healthcare costs too much. As providers of care, Baptist Health has the responsibility to lead industry efforts to increase quality and decrease costs. There are tremendous opportunities for hospitals, payers, and physicians to align and collaborate to develop and implement the foundations necessary to accomplish these sea changes, and Baptist Health desires to be at the forefront of these important changes,” he said, including doing what he called “the right thing,” such as reducing hospital lengths of stay and performing traditionally inpatient procedures in outpatient settings.

	“As the CFO of the largest not-for-profit healthcare system in South Florida, I can tell you with certainty that doing the right thing often times translates to lower reimbursement for the hospital,” he said, adding, “but, there is no doubt in my mind, we as an industry must do the right thing, and arrangements like this allow us to do just that.”

Integrative model unites physicians, hospitals, and payers to deliver evidence-based care and control cancer costs.

Accountable Care Organizations Come to Oncology

		Scanning electron color-enhanced image depicts prostate cancer cells.

Photo courtesy Annie Cavanagh/Cell Image Library

	With more than 240,000 new cases expected in the United States in 2012, prostate cancer is among the nation’s most common tumor types.

 And yet despite its prevalence, treatment decisions remain fraught with controversy. From solo oncology practices to technology-filled cancer centers, physicians and their patients continue to grapple with wrenching and fateful decisions over the disease’s management.

	A 2009 National Cancer Institute (NCI) study

 showing that annual screening for prostate cancer led to more diagnoses but no fewer deaths starkly illustrates the conflicts. Some patients benefit little from the surgery, radiation, and other treatments prompted by their diagnoses, the NCI noted, while suffering debilitating adverse events such as incontinence and impotence.

	Faced with these high-stakes choices, a growing number of physicians are turning to predictive tools called nomograms to help them gauge more precisely how a patient’s cancer is likely to progress and to better assess the chance of a cure through a given treatment.

	Derived from institutional databases that include clinical and outcomes data for anywhere from hundreds to thousands of patients, these formulas consider multiple factors such as prostate-specific antigen (PSA) levels and Gleason scores—weighted to reflect their relative contribution to a particular outcome&mdash;to calculate a patient’s pathologic stage, chance of recurrence, and likelihood of a cure, among other results.

	“We use nomograms as an important part of the education of every patient,” said James Mohler, MD, associate director and senior vice president for Translational Research and chairman of the Department of Urology at Roswell Park Cancer Institute in Buffalo, New York. “They really help men assess their pathologic stage and cure rate.”

	Now widely available on the Internet, nomograms enable patients weighing treatment options to plug in their own clinical data and receive the probability of an outcome, such as the likelihood that their cancer is organ-confined.

	The widening use of nomograms, however, has drawn the scrutiny of some skeptics, who question their predictive power and urge patients and physicians to closely examine the data from which they are derived. Those who embrace them insist that their ability to harness the predictive power of data represents a huge advance over anecdotal evidence.

	Patients’ Questions Led to Development

	Alan W. Partin, MD, PhD, director of the Brady Urological Institute at Johns Hopkins Medicine in Baltimore, Maryland, and a pioneer in the field, recounted his patients’ hunger for more precise assessments of their cancer and their frustration over the lack of it.

	“When we would talk about risk with patients, they would ask us, ‘How good is good? Are we talking about 10% good or 90% good?’ “ recalled Partin, who 2 decades ago began to examine information from a large group of men “with similar blood tests, exams, and pathology reports” who had undergone radical prostatectomies at Johns Hopkins “to see how the cancer had spread.”

	In 1993, he and Patrick C. Walsh, MD, then the institute’s urologist-in-chief, developed probability tables known as Partin tables by correlating 3 key pieces of information—PSA level, Gleason score, and estimated clinical stage&mdash;with patients’ actual pathologic stage. The tables perform what the institute calls a “virtual surgery” by allowing physicians to predict what would be found if the prostate were removed surgically and examined by a pathologist.

		Flow chart shows broad categories in The Partin Tables. (James Buchanan Brady Urological Institute website, 

http://urology.jhu.edu/prostate/partintables.php

	Updated periodically to reflect current data, and based on the results of more than 5000 men who underwent surgery at Johns Hopkins, they have been shown to predict with 95% accuracy a man’s likelihood of being cured by treatment.

	“I use them with every patient. I tell patients that they have come in with three tests and that we will compare them to other people with similar data,” Partin said in an interview. “If options exist, that’s when we use nomograms, typically right after diagnosis, to determine how far the cancer has spread and how many years a patient will survive disease-free after a particular treatment. Nomograms are very useful in predicting when cancer is organ-confined and help us make decisions about whether to perform surgery, for example.”

	He added, “The healthcare arena, and particularly the people who are paying for treatment, will likely rely on these metrics more and more to decrease the chance of unnecessary treatments being offered.”

	Since the Partin tables were developed, researchers have devised predictive models that incorporate even more variables, while exploring more endpoints and outcomes, including the probability of treatment success for salvage radiation therapy for men who have experienced prostate cancer recurrence after a radical prostatectomy.

	“What nomograms do is strive for more precision,” said Michael Kattan, PhD, chairman of the Department of Quantitative Health Sciences at the Cleveland Clinic in Ohio, who has developed some of the most widely used nomograms, including models that predict the probability that a cancer will be indolent.

	Kattan said it was his own brush with oncology’s lack of predictive capability that inspired his interest.

	“I was in a PhD program in business school and was diagnosed with Hodgkin disease. As I faced questions about treatment—whether to choose radiation on top of chemotherapy&mdash;I looked for predictions to help me and found they were not there. In the world of business, predictions are everywhere, but in medicine, the field is still immature,” said Kattan.

	In developing nomograms, he added, “I wanted to be able to plug in actual patient values.”

	He accepted a postdoctoral fellowship in 1993 in medical informatics at Baylor College of Medicine in Houston, Texas, and later that year teamed up with Peter T. Scardino, MD, who is now the chairman of the Department of Surgery at Memorial Sloan-Kettering Cancer Center in New York City, to create new models.

	“We’ve come a long way toward recognizing the need to incorporate individual patients’ preferences into decisions. The one-size-fits-all model in prostate cancer doesn’t work for individual patients,” Kattan said.

	Nomograms are most helpful when the decision-making is most difficult.” ”

	“Nomograms are most helpful when the decisionmaking is most difficult, when there are trade-offs, for example, between quality of life and quantity of life or when comparing one side effect to another,” he said. “They are not that useful if there is only one treatment for a disease.”

	He noted that in prostate cancer alone there are “a couple hundred now and they predict further into the future and incorporate new biomarkers. Data such as a man’s outcome two years after treatment is one refinement. Endpoints have been added that go beyond just recurrence, such as quality of life, including the effects of toxicity.”

	Some oncologists view nomograms with caution, however, particularly as they have proliferated.

	“They’re very seductive. One can go to a Website and plug in a few numbers and a percentage regarding outcomes comes out. It seems so simple and accurate, but there is no way to predict with 100% certainty how well a given patient will do. For example, a more advancedstage patient may do well despite the low percentages given by the nomogram,” said Andrew K. Lee, MD, MPH, associate professor in the Department of Radiation Oncology at the University of Texas MD Anderson Cancer Center in Houston and director of its Proton Therapy Center.

	Some nomograms, he added, have wide confidence intervals that undermine their accuracy.

	“Say the nomogram predicts a risk of 76%, that number could actually have a range of 65% to 89%,” Lee said. “These models may also perform differently in terms of where within the nomogram a patient falls. The variables you put in for your patient may turn out to be a constellation of numbers that never existed in that data set. The nomogram may work well for more typical numbers, but may not perform as well with outliers. It tries to make a prediction by extrapolating from the data it has.”

Journal of the National Comprehensive Cancer Network

, Lee described a nomogram for brachytherapy that had underperformed.

	He said in an interview that he was more broadly concerned that the models are based on “retrospective data that are prone to selection biases we can’t always discern.”

	“We cannot know, for example, why a given patient opted for surgery over radiation. There may have been other factors that influenced the choice. Unknowns like that can taint retrospective data. It’s not the same as running a randomized trial, which accounts for known and unknown confounding variables,” Lee said.

	Lee recommended that oncologists examine nomograms in the context of their clinical experiences. “A physician may not have the time to validate them, but they should be tested for how well they perform within one’s own practice,” he said.

		Micrograph shows Gleason pattern of a prostatic acinar adenocarcinoma.

	Kattan, Mohler, and others agree that nomograms are only as good as their databases.

	“We must be careful about nomogram quality. If confidence intervals are wide, such as in unusual clinical situations where there are not many people like you, or when nomograms are constructed from a small database, they don’t function as well and may not be accurate enough to really provide much help to an individual patient,” observed Mohler, who chairs the National Comprehensive Cancer Network (NCCN) Prostate Cancer Treatment Guidelines Panel.

	The data, Kattan said, must be carefully collected.

	“Say you need to plug in the patient’s presurgery PSA value, but there are several in the chart collected over time. If you’re doing this in a hurry, you may just pick one of them and it may not be the right one,” he said. “Also, you need to follow patients after surgery, but they don’t always come back.”

	Kattan acknowledged that the availability of nomograms has complicated treatment discussions for some physicians.

	“The proliferation of nomograms has put pressure on doctors. It’s their decision whether to trust them or not. Sometimes publications are linked to them and so the data can be evaluated,” he said, adding, “Not all community oncologists use them. Some do and some don’t. It makes visits longer and adds variables to the decision making.”

	But nomograms become more reliable as data collection, performed mostly by high-volume institutions, researchers who organize clinical trials, and occasionally pharmaceutical companies, continues to improve as interest in risk assessment grows, he said.

	“The desire to predict more outcomes will demand more and better collection of data,” said Kattan. “What will probably help us do a better job are electronic health records that allow us to collect data more efficiently. If we use them wisely and meaningfully, these databases are useful for research as well as patient care. We need to change the way we think. Data collection is the biggest hurdle, not the lack of wizard prediction models or supercomputers.”

		Tools for Assessing Risk in Prostate Cancer

	The National Comprehensive Cancer Network recommends that the risk stratification scheme in its guidelines be used to gauge a patient's risk level. Nomograms should be used to "provide additional and more individualized information."

	Here are several of the better known nomograms used in prostate cancer treatment:

					7 prostate cancer nomograms are among 19 calculators for oncologic and other diseases

http://www.lerner.ccf.org/qhs/risk_calculator

					James Buchanan Brady Urological Institute at Johns Hopkins Medicine

					The Partin Tables and the Han Tables are available

http://urology.jhu.edu/prostate/hanTables.php

					Memorial Sloan- Kettering Cancer Center

					7 calculators for prostate cancer patients, including a tool that analyzes average male life expectancy, are offered

http://nomograms.mskcc.org/Prostate/index.aspx

	He added, however, “It takes a lot of time and money to do this accurately, and it’s hard to get funding for it. These funds are not coming from the government or insurance companies, so the task is falling on the backs of academically oriented researchers. It’s an unfunded mandate.”

	Partin has already updated his own tables 2 times. “The disease has evolved because of early detection and so the probability distributions have changed,” he explained.

	Mohler noted that the first NCCN prostate cancer treatment guideline, published in 1997, referenced the Partin tables in the manuscript section. By 2003, their use was common, and many academic researchers thought they should be added to the guidelines to encourage and facilitate ease of use. The guidelines now reference 11 nomograms, but strongly encourage the use of only the Partin and Kattan nomograms at this time, he said.

	“We include nomograms in guidelines if the data have been collected well,” said Mohler. “Typically, data sets are from individual institutes’ experience. They are tested and evaluated elsewhere. Memorial Sloan- Kettering has historical and current versions of its nomograms. The historical nomogram has been vetted by many institutions. When I counsel patients, I give the current and historical versions. We’re running both through the Roswell Park population to test how well they apply to our particular patients.”

	Institutions test a nomogram’s accuracy by running their database through it to see how well it predicts the outcomes of their patients.

	“If it doesn’t do well, you test other available nomograms or develop your own,” Mohler said, adding, “I use radiation nomograms more casually because they’re not as mature as some others. I’m just starting to use nomograms for salvage radiation therapy. We want to deliver our patients more information but these nomograms have not been vetted by as many institutions, and we all know that we need better databases that will in turn result in better nomograms.”

With more than 240,000 new cases expected in the United States in 2012, prostate cancer is among the nation's most common tumor types.

Predicting Prostate Outcomes: Nomograms Help Patients Sort Options, But Caution Is Urged

As the Centers for Medicare & Medicaid Services (CMS) deliberated earlier this year over whether to cover Provenge (sipuleucel-T), an expensive but potentially gamechanging new treatment for prostate cancer, many in healthcare policy, patient advocacy, and oncology circles held their breath. Would the agency reject a cancer treatment approved by the FDA?

	In late March, CMS ended the speculation by announcing its intention to pay for onlabel uses of the drug, which costs $93,000 for a 3-dose regimen, while leaving off-label coverage decisions to its regional contractors. More recently, the agency issued a final National Coverage Determination that requires Medicare contractors to cover Provenge’s use in treating asymptomatic or minimally symptomatic prostate cancer that has spread to other parts of the body and is resistant to standard hormone treatment.

	Despite the outcome, CMS watchers called the controversial review significant, with possible implications for policy decisions down the road.

	J. Leonard Lichtenfeld, MD, deputy chief medical officer for the American Cancer Society, described it as “the preliminary round in a heavyweight match-up between Uncle Sam and the pharmaceutical companies.”

	“One wonders why they went through the process if it were not about cost,” he said. “From a purely practical point of view, this was a straightforward decision. The drug had shown benefits, had the approval of the FDA, and so it would have flown in the face of decisions the agency had made previously to deny coverage.”

	But he noted that the agency had already signaled its sensitivity to costs by refusing to pay for cancer tests.

	Indeed, Lichtenfeld said that CMS “threw down the gauntlet” in 2009 in denying coverage of CT colonography for the detection of colorectal cancer. The agency made it clear following that decision, he said, that assessing the value of treatments and their impact on the Medicare budget were within the scope of reviews.

	“The agency declared an aggressive public policy intended to put the brakes on approvals, and the decision was written in a way that suggested it was within their purview to ask [for] more details. I thought this time might be the time CMS would exercise that newfound authority,” he said, noting however that he agreed with the decision to cover on-label uses of Provenge.

	One wonders why they went through the process if it were not about cost. From a purely practical point of view, this was a straightforward decision. The drug had shown benefits, had the approval of the FDA, and so it would have flown in the face of decisions the agency had made previously to deny coverage. ”

	“But I think we missed an opportunity to take on questions about off-label use,” he added. “I expected CMS to say ‘no’ to off-label use, except as part of clinical trials. That did surprise me.” Lichtenfeld commented on his blog that such an open-ended policy could subject the local carriers to a deluge of men “seeking this treatment for all the wrong reasons: very advanced symptomatic disease all the way to men newly diagnosed with their cancer, or whose cancer has spread but still responds to hormone treatment.”

	While the decision ultimately backed existing healthcare policy, it infused uncertainty into the process that is unlikely to dissipate soon, said Allen S. Lichter, MD, chief executive officer of ASCO.

	“I don’t know whether we’ll see this again or will get it with every single new cancer agent,” Lichter said, adding that such ambiguities in the approval process pose a threat to both care and research. “If you’re a drug developer, the possibility must be factored in as a risk of making the investment. It injects uncertainty no matter what you do, and this is the specter this process has raised.”

	When CMS announced the review last year, ASCO urged the agency to withdraw from it on principle, noting a lack of “clarity regarding the purposes underlying this action” and asserting ASCO’s belief that the Social Security Act requires CMS to cover drugs and biologics for FDA-approved indications used in anticancer chemotherapeutic regimens.

	“We understand that the cost of cancer therapeutics is increasing at a steady and relentless pace and that it can’t continue at that pace,” Lichter said. “But if you want to change the rules, you cannot use a single drug to have a discussion that needs to be held at a different level and a different place. We think CMS should always pay for FDA-approved agents.”

	He added, “We would love to see a clear and strong statement from CMS that would reaffirm that on-label use of FDA-approved drugs is provided coverage. Do I expect we will see such an affirmative statement anytime soon? No. It is to their advantage to keep options open.”

	Lichtenfeld, who also described the recent decision as “leaving us no clue about where we’re going on these issues,” said that future budget limitations might force the government’s hand.

	“Expensive drugs in a budget-neutral situation impact how much is available to pay for other services,” he said. “Inevitably, as a society, we will be forced to make some cost decisions. When there is an absolute limit on the amount of money Medicare has and patients’ services are impacted, and when things become so tight that patients can’t get in the door, that’s when we’ll see restrictions.”

	To date, Lichtenfeld added, the only place where costs are flexible is in Medicare Part B, the payments to physicians.

	We understand that the cost of cancer therapeutics is increasing at a steady and relentless pace and that it can’t continue at that pace. But if you want to change the rules, you cannot use a single drug to have a discussion that needs to be held at a different level and a different place. ”

	“There is no other place to go because we can’t negotiate with the companies that provide drugs. Doctors, coping with declining reimbursements, are already saying ‘no’ to Medicare patients,” he said, adding that it is patients, who pay 20% of the price of drugs, who are most impacted by rising costs.

	Lichter said the practice of oncology has also been “tremendously affected.”

	“The need for physicians to counsel patients financially, to intrude into the pure relationship is increasing,” he said. “In some cases, patients who cannot afford drugs don’t take them, and in others, they’re being sent from community practices to hospitals.”

	And while there is still no clear basis in the law for government regulators to take costs into account, he added that “private insurers are wrestling with this all the time. With restrictions and prior approvals, the issue in the private insurance sector is the extent of coverage. It may not be as clear as simply refusing to pay.”

	Anger and frustration over what some patients and investors saw as prolonged and opaque regulatory reviews of Provenge spilled over into politically charged protests.

	“We thought the agency should have been clearer about what the review was for, and we questioned whether they should do a review at all on a late-stage cancer drug after FDA approval. Late-stage cancer is the wrong illness to target,” said Kerry M. Donahue, attorney for Care to Live, an advocacy group composed of patients, doctors, and investors that was formed in 2007 after the FDA initially withheld approval of Provenge, requiring additional trials.

	Had CMS denied coverage, “there would have been thousands of people protesting in front of their offices,” he added.

	Donahue said that it became clear early on in the process, however, that neither Congress nor the courts would insert themselves into the approvals process.

	“We appealed to members of Congress to intervene after the FDA’s initial decision, citing a conflict of interest on the part of board members, but were told they couldn’t because it was an ongoing process,” he said. “We then took the complaint to US District Court for the Southern District of Ohio, which turned us down, and that decision was then affirmed on appeal.”

	Donahue called the lengthy reviews by the FDA and CMS troubling, both from the standpoint of patients and the drug development process. “This was a small company that came up with something novel,” he said. “Having that investment in immunotherapy research is so important to cancer research.”

	Lichter said the oncology community is not sitting on the sidelines as costs escalate, but is exploring various means to deliver treatments both effectively and efficiently.

	“Pretending cost isn’t an important issue is not realistic,” he said. “When does a line get crossed? Is it $50,000 or $200,000? We need to take away taboos of talking about costs. Unless we say the budget is unlimited, at some point someone has to say ‘no’ to something.”

	Lichter noted that ASCO formed a costof- care task force 3 years ago that includes representatives from a wide spectrum of stakeholder groups that are looking at ways to rationalize the process: to obtain needed drugs, to improve cancer treatment, and to keep costs in check.

	He described the use of biomarkers to identify which patients are likely to respond to a drug so it is used more efficiently as another method, noting that “many new drugs are now coming out with companion biomarkers.”

	Lichtenfeld said regulators also have additional tools at their disposal to control spending.

	“We recognize that there are serious considerations about how to put resources to better use,” he said. “We felt on good authority, for example, that in the case of CT colonography, that CMS could have covered the tests with evidence and collected data that would have either validated the procedure or validated concerns. We thought this could have been a new paradigm and an innovative way to move forward.

	“By carefully examining outcomes when there are significant coverage questions, such as how to use the medicine properly and most effectively, it’s beneficial to examine the reallife impact of treatments,” said Lichtenfeld. “We can do this if patients agree to be followed and monitored. We have learned from that experience.”

In late March, CMS ended the speculation by announcing its intention to pay for onlabel uses of the drug, which costs $93,000 for a 3-dose regimen, while leaving off-label coverage decisions to its regional contractors.

Value-Based Coverage Decisions: CMS Scrutinizes Provenge

	In 1977, when Dr Jimmie C. Holland was approached by the legendary Lewis Thomas, MD, then the head of Memorial Sloan-Kettering Cancer Institute, to establish the first full-time psychiatric service at a cancer research hospital, she arrived with a deep and longstanding interest in the nascent field, but no roadmap to guide her.

	“We started with an open mind,” recalled Holland, who was then a psychiatrist at Montefiore Medical Center in the Bronx, New York. “We weren’t sure what we could do. There were few studies to guide us. We were learning too. We did not know, for example, whether psychotropic drugs would help with depression in the context of serious physical illness. We began to generate our own research to answer these questions.”

	At the outset, she and her team encountered skepticism on the part of some oncology colleagues about the need for psychiatrists in cancer hospitals, which were for the most part then staffed with social workers, but not mental health professionals.

	“We got a mixed reaction at first,” she recalled. “We struggled with this for years. Some oncologists appreciated the need, but others did not see the concern for psychological and social problems as a part of oncologic care.”

	But Holland was long convinced that psychological status was a critical factor not just in cancer management, but in illness more broadly.

Dr Jimmie C. Holland was long convinced that psychological status was a critical factor not just in cancer management, but in illness more broadly.

Tracey Regan

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