Targeted Therapies Lead To Exciting Improvements in the Treatment of Melanoma Patients

Melanoma is the most virulent form of skin cancer with a rapidly rising incidence due to prior sun exposure. About 40,000 men and 30,000 women per year in the USA develop melanoma. In addition to sun exposure, there are independent genetic risk factors such as a variation in the “red hair” gene that increases in frequency the further one’s ancestral home is north of Africa.

Melanoma, as with all cancers, has its own genotype variations. There are at least five melanoma genotypes which can be detected with molecular profiling (for more information look at Vanderbilt’s “My cancer genome”). Each type has its own different mutations.

Just fewer than 50% of melanomas have a mutation in BRAF, a cell signaling pathway. Approximately 90% of the BRAF mutations produce a substitution of glutamic acid for valine at codon 600 in the gene product. This is apparently a critical factor in the development and aggressiveness of melanoma cells. About 20% of melanomas have an NRAS mutation, 1% have both BRAF and NRAS and 30% have neither mutation. Interestingly, among patients 20-30 years old, 86% will have the BRAF mutation but only 22% of those over 70 years have it. As a result, the new drugs that target the BRAF mutation gene product will be of relatively more utility in younger than in older individuals.
One of the new targeted drugs is an inhibitor of the BRAF mutated gene product called Vemurafenib – the name based on “V600E mutated BRAF inhibitor.” Vemurafenib (Zelboraf) decreased the relative risk of death by 63% and the risk of tumor progression by 74% when combined with dacarbazine (an alkylating agent also known as DTIC or imidazole carboxamide which has been the long time standard of care for metastatic melanoma) compared to dacarbazine alone in a large cohort of patients with the BRAF V600E mutation in their melanoma. The FDA approved this drug for treating melanoma in August, 2011 for BRAF mutation positive patients as determined with a companion diagnostic device called the BRAF V600 Mutation Test.
In this phase 3 trial of 675 patients, there as 48% response rate and a 5.3 month median progression free survival with Vemurafenib compared with dacarbazine with its 5% response rate and 1.6 month progression free survival median. Exciting as this sounds, it is no panacea and certainly not a cure although some patients had both excellent tumor shrinkage and long survivals, both rarely seen with dacarbazine. Side effects were acceptable but squamous cell skin cancers developed in some and activity declined over time. To deal with the latter, new trials are evaluating combined targeted therapy by adding a MEK gene product inhibitor. In early results, there was increased activity and fewer skin tumors developing.
The cost, according to the manufacturer, Genentech, will be about $60,000 for a course of therapy over about six months. Vemurafenib tends to have rapid responses and so might be especially important for patients with extensive disease or severe symptoms. Despite the enthusiasm for a drug that actually has real benefit, it is not curative therapy nor does it produce truly long lasting responses. Still it is a major improvement and offers real benefits and hope to patients, a testament to the concept of targeted therapy based on genomic information.
Another drug, ipilimumab (Yervoy) also has shown substantial activity against metastatic melanoma. Ipilimumab is a monoclonal antibody that binds to the cytotoxic T-lymphocyte antigen 4 (CTLA 4) and acts to enhance T-cell activation. In other words, it activates the immune system. It was approved by the FDA in March, 2011. The basic clinical trial that led to approval had 502 poor prognosis patients yet with good performance status. Patients randomized to ipilimumab plus dacarbazine had a longer time of progression free survival and the responses that developed persisted longer (19.3 vs. 8.1 months) than those who received dacarbazine alone. Overall survival was 11.2 months compared to 9.1 months but there were about 25% alive at four years which is quite noteworthy. Unfortunately, it can cause or exacerbate autoimmune disease because it allows T-cells to stay activated. The manufacturer, Bristol Meyers Squibb, at the request of the FDA, has sent a booklet to all medical oncologists to guide attention to these potentially serious side effects. It costs about $120,000 for a course of treatment.

So these are encouraging improvements for a tumor that has been exceptionally resistant to new approaches to treatment over the years. The key has been to understand the genetic mutations in the tumor, then to analyze the gene product and finally to create a drug that inhibits the gene product’s activity – genomic targeted therapy. Going forward, treatment will probably be a combination of compounds that interact with various mutations’ effects, hopefully augmenting the activity shown by these two drugs to date.

Primary Care Physicians Can Greatly Reduce The Costs Of Care, Especially For Chronic Diseases

In an earlier post I described the problem of excessive and inappropriate drug prescribing when a patient with multiple chronic illnesses did not have good care coordination by a single primary care physician. In this post I will relate the story of a lady who had an excellent primary care physician but the communication system broke down when she went elsewhere for a single visit. In her case the problem was the recommendation of an inappropriate medical technology for her chronic condition.

Ellen is an elderly lady who had been going to the same primary care physician (PCP) for over twenty years. On nearly every visit she said that she felt “tired.” Repeated history and exam revealed no cause nor did logical tests such as those for anemia or hypothyroidism. She then developed syncopal episodes – times she would black out and fall to the floor, once bruising her head when she fell against the stove, and then waking up in a few minutes. Evaluation showed that she had intermittent episodes of bradycardia, or very slow heart rate, resulting in the drop attacks. In consultation with a cardiologist, it was decided to insert a single lead pacemaker. The pacemaker senses the electrical action in the heart and when the rate drops below a set level, it immediately begins to send out an electrical stimulus – on demand - to the heart muscle so that it will contract at a normal rate. The pacemaker is expensive and the procedure to place it is expensive as well. But it worked perfectly and she no longer had the attacks that were not only scary and medically dangerous but seriously impacting her quality of life. A good return on investment.

A few months later during a visit to her daughter, she went to that daughter’s internist for an unrelated reason; he urged her to see a cardiologist colleague. Both the internist and the new cardiologist heard the usual complaint of “being tired” and assumed it related to her cardiac status. This cardiologist in turn recommended that she needed a “dual lead” pacemaker instead of the single lead one she had. [It has been found that having more than one lead can sometimes improve the heart’s output for very carefully selected patients with heart failure.] When the PCP much later received the cardiologist’s mailed consult report, he disagreed, noting she did not have heart failure, just syncopal attacks – an electrical not a mechanical problem in her heart. Further, the current pacemaker was only needed about 10% of the time meaning that her heart beat at a normal rate at least 90% time, so the pacemaker was not even active most of the day. This lady did not need the proposed new, even more highly expensive pacemaker. No pacemaker, no procedure, no risk of insertion, no risk of post operative infection or bleeding. A lot of money could be saved and the patient could be spared a straight forward yet somewhat risky procedure – which she did not need. The fundamental problem was the lack of care coordination. One would like to believe that had her medical record been easily available digitally, the newly involved internist would have never even suggested the need for a cardiologist opinion and even if sent on, the cardiologist would have rapidly recognized the lack of need for the new device.
The lesson is one doctor needs to be the orchestrator of all of the patient’s care. A good PCP, like this one, coordinates the care of his or her patients with chronic illnesses and in so doing avoids excess referrals, tests, procedures and hospitalizations along with unneeded drugs or devices – all the elements that drive up the total cost of care – and in the process assures quality care, safer care and a close doctor-patient relationship. But sometimes a patient is elsewhere, sees a new physician and the medical history is not readily available. All too often as in this case, the patient ends up getting tests, images or procedures that he or she just does not need.
One of the most effective ways to reduce medical care costs is with good coordination of the care of individuals with chronic illnesses. As the story of Ellen above and of Henry from the earlier post exemplify, there is a strong tendency today for patients with chronic illnesses to either be referred to various specialists or else to go on their own. When this occurs without coordination, the visits add up, the number of tests and images ordered go up, the number of drugs prescribed rises rapidly and the number of procedures and even hospitalizations climb. Unfortunately, many of these are simply not needed – excessive and wasteful, not the best quality and obviously very costly. The value of a good digital medical record in both of these patients is obvious because communication among providers is critical to optimal care.

The primary care physician is in the best position to coordinate care. He or she knows the patient, the patient’s family and socio-economic situation and of course the patient’s various illnesses. Ellen did not need to see a second cardiologist and did not need the dual lead pacemaker. The PCP knew that “tired” was just her normal statement at every visit; not a reason to do more tests, add a drug or do a new procedure. It was unfortunate, indefensible but not at all uncommon that the new cardiologist did not make the effort to call the long time PCP. It would have been quickly determined that Ellen did not need a very expensive new pacemaker.

Henry suffered because he did not have a PCP. Instead he had four doctors, each one dealing with all of his problems and none communicating with the others. Once he had a single PCP, his prescriptions plummeted from 23 to seven, he felt better, had fewer drug-induced side effects and both he and his insurers were saving a lot of money.

Care coordination is critical; it improves the quality of care; it reduces risk; it reduces the costs of care; and it ultimately improves patient satisfaction. A good PCP (or occasionally a specialist) is needed to the orchestrator of that coordination. The electronic medical record has an integral part to play in robust care coordination.
Why, with all of these attendant advantages, do not all PCPs engage in excellent care coordination? I believe it is twofold – dollars and lack of training.

My new book, “The Future of Health-Care Delivery: Why It Must Change and How It Will Affect You,” from which this post is adapted, will be published in February, 2012 by Potomac Books

Care Coordination Is Critical For Those With Chronic Conditions Like Diabetes or Osteoarthritis

This is the fourth post in a series on care coordination; this time focusing on other examples of team-based care. Patients with diabetes not only have to deal with the diabetes itself and its management, such as insulin and drugs, but they have to deal with nutrition, weight and exercise. They need to cope with potential side effects of the diabetes, such as damage to their eyes or kidneys or the blood vessels running into the lower legs that can lead to ulcerations, infections and even amputations. The current approach is for an internist to be the patient’s primary care physician and then to send the patient on to a specialist whenever a problem arises. A much better approach is the one developed by the Joslin Clinic in Boston, which has now been “franchised” across the country. The internist refers the patients to a Joslin Center for consultation. There the patient has a nurse as their coordinator and advocate, an endocrinologist to work out the specifics of their diabetic drugs and insulin, an exercise physiologist to help them with an exercise plan, a nutritionist to review their dietary needs, an on-site ophthalmologist expert in diabetic complications of the eye, and a podiatrist to deal with foot issues. The point is that all of these professionals are available in a single location. The patient comes to one place and one place only and from there can go to individual adjacent offices to see whomever they need to see. Whenever they come back to see, say, the exercise physiologist, if there is an issue or problem they immediately can be referred across the hall to the appropriate specialist. They key is that these healthcare providers are all working as a team and bring to bear all of the different disciplines necessary to the treatment of this complex and complicated disease for this individual patient. And by using an electronic medical record, the data is all present all of the time as the patient goes from one provider to another within the Center but also back home with his or her primary care physician. The result is better care, more coordinated care and a much more satisfied patient. It also costs much less because there is less duplication, less unnecessary testing or X-rays, and fewer hospitalizations because the patient is better cared for.


So as time goes on, more and more of these disease-based programs will emerge for the care of complex, chronic diseases. To some degree this may seem to threaten the primary care physician in the community. But it is really a benefit and an adjunct to both the physician and the patient. The primary care physician still sees the patient for the bulk of their individual care but knows that he or she and the patient have an expert team available to help either occasionally or more often as necessary.

Here is an example of team based care in orthopedics. Marshall Steele, III, MD is an orthopedic surgeon in Annapolis, Maryland who did a lot of knee and hip replacements. He was frustrated that the system just was not efficient nor was it patient or provider friendly or convenient. So he and some collaborators worked with their hospital, Anne Arundel Medical Center, leadership to devise a totally new approach to total joint replacement. Briefly, it works like this. A unit of the hospital was set aside solely for total joint replacement patients with its own dedicated staff. A single leader who had full responsibility but also the needed authority was placed in charge, eliminating the traditional silos that exist in most hospital management systems. Instead of being focused entirely on the inputs which dominates organizations structured in departments, this new model focuses first on the outputs (outcomes) of their work from the perspective of all stakeholders. All patients for the week are brought in the week before to meet each other, meet the staff, tour the facility and attend a class taught by a nurse navigator or coordinator of what will transpire during their stay. They are then all brought to the hospital for surgery the same day, necessitating that extra ORs be available for the orthopedists. After surgery the patients are put into a wellness environment outside of their hospital room. There they are brought together for some meals each day and for beginning physical therapy. They even return as outpatients for physical therapy together.

These steps plus many others have markedly improved physician, nurse and physical therapist coordination and satisfaction while working as a multi-disciplinary team, each with their own expertise unleashed for the care of these patients. The patients are much more satisfied and work together as a support group. At a formal luncheon one month later, patient and family input is sought and programs changed to respond to their needs and those of their families. Length of stay is down and complications have been reduced. Important hospital reported metrics are collected and shared with the team on easy to understand electronic dashboards. Patient reported metrics are collected on how effective the procedure was in reducing pain and return to desired activities. As word got around, more and more patients, many from great distances, sought out the team. Hospital revenues rose and the orthopedists became very busy. Other hospitals have tried to emulate this approach. But many fail. Why? Because, as Dr Steele points out, what is needed is a transformational change but most physicians, hospital staff and hospital managements are only able to muster incremental change. Incrementalism where transformation is needed just doesn’t work.

As medicine becomes more and more disease/patient-oriented, the traditional departments of medicine and surgery within a hospital will tend to be de-emphasized and in their place will come centers for cardiac care, cancer care, diabetes care, stroke care, joint replacement and the like. A multidisciplinary team approach to care will become much more common. Just as with the primary care physician, this shift will appear to many practicing specialists to be a “threat” to their autonomy and certainly to their long-held practice patterns. To be effective they must have an effective electronic medical record system. Moreover, insurers do not like to pay for a team to see a patient. Their approach is to pay one physician for one consult or one patient visit. To pay for three doctors to see one breast cancer patient all at once is anathema, and, in general, they may refuse payment. Hospital managers, like physicians, are “conservative” and traditional, with functions organized in a format that was effective many years ago but which is no longer. But change is difficult and as pointed out in the story above on joint replacement, the change needed is transformational, not incremental. The electronic medical record, critical to success of these arrangements, must be part of the transformational change. Change will not come easily; but it must occur and so it will, but not quickly. But the hospitals who figure this out first will have a competitive advantage.

These stories raise the question as to why it is so difficult for physicians and hospitals to change their ways when the new approach can be shown to be so much more effective in delivering improved quality of care at a reduced cost?

My new book, “The Future of Health-Care Delivery: Why It Must Change and How It Will Affect You,” from which this post is adapted, will be published February 28, 2012 by Potomac Books. You can find it now at Amazon at http://tinyurl.com/