Outliving Hospice

Outliving CancerFor those of you who have read my book Outliving Cancer you will recognize the chapter entitled “Outliving Hospice.” It is the description of one of my lung cancer patients.

The saga began in 2005, when this gentleman with metastatic lung cancer under the care of the Veteran’s Administration in Los Angeles presented to our group requesting a biopsy for an EVA-PCD assay to select therapy. Diagnosed some months earlier his lung cancer had progressed following first line platinum-based chemotherapy. He was deemed untreatable and placed on hospice.

At his request, one of our surgical colleagues conducted a biopsy and identified a treatment combination borrowed from work done some years earlier by Japanese investigators. It worked perfectly for a year allowing him to return to a normal life.

At year two however, he relapsed. At that point, we confronted a dilemma – would we accept the inevitability of his progressive disease, fold our tent, and allow the patient to return to hospice care; or conduct yet another biopsy to determine the next line of therapy? If you have read the book, then you know how the story plays out. The new biopsy revealed the unexpected finding that the tumor had completely clocked around to an EGFR-driven cancer, highly sensitive to erlotinib (Tarceva). Placed upon oral Tarceva, he has been in remission ever since.

When I saw Rick, two weeks ago at our six month routine follow up he provided a copy of his February 2014 PET/CT scans which, once again, RickHelm Small Imagerevealed no evidence of progressive disease. With the exception of the skin rashes associated with the therapy, he maintains a completely normal life. During our discussion he apprised me of an interesting fact. His survival, now approaching 10 years, according to him, constitutes not only the longest survivorship for any patient under the care of the Los Angeles VA, nor any patient under the care of the VA in California, no, he is the longest surviving actively treated metastatic non-small cell lung cancer under the care of the Veteran’s Administration. Period! While I cannot, with certainty, vouch for this fact, I am quite certain that he is among the best outcomes that I have seen.

There are several points to be gleaned. The first is that every patient deserves the best possible outcome. The second is that hospice care is in the eye of the beholder. The third is that patients must take charge of their own care and demand the best possible interventions available. As an aside, you might imagine that a federal agency responsible for the costly care of tens of thousands of lung cancer patients every year would pay attention to results like Rick’s. Might there be other patients who could benefit from Ex-Vivo Analysis for the correct selection of chemotherapeutics?  One can only wonder.

Two Women with Metastatic Breast Cancer – Same Age, Same Disease, Two Very Different Functional Profiles

A day in the life of advanced breast cancer. Two different 37-year-old breast cancer patients, both mothers of young children, were seen in consultation on the same day.

The first had been referred by a colleague who was concerned that the patient’s ER positive breast cancer had disseminated to her brain despite aggressive standard chemotherapy. She was to undergo a craniotomy and a portion of fresh tumor would be submitted from the surgery to Rational Therapeutics for EVA-PCD functional profiling.

The second mother had metastatic triple negative breast cancer, which recurred after aggressive standard chemotherapy. She underwent neo-adjuvant treatment (preoperative) but at the time of her surgery, there was no evidence of response to the treatment. By the time we met her, only months into her diagnosis, new areas of metastatic disease were cropping up daily.

Microscope Detail2-lo resThe EVA-PCD assay results on these two “similar” patients were entirely different.

The results of the first patient with the ER positive tumor and brain metastases clearly identified treatments directed toward the PI3K pathway, with or without chemotherapy. We are recommending a combination of Everolimus plus chemotherapy.

The second patient had a completely different profile. Indeed, the degree of drug resistance was quite striking. A three-drug combination was among the most active from almost two dozen drugs tested.  The other option appeared to be a new class of drugs called the cyclin dependent kinase (CDK) inhibitors.

On a functional level, we used targeted drugs to probe for sensitivity to inhibitors of these cancer signal pathways. Unlike genomic profiles that tell you whether the gene is present or absent, we can tell whether the gene is driving the tumor. Functional profiling.

One patient is now under my care and the other will begin treatment under the care of a colleague in Orange County, CA. We will await results of these assay-directed therapies and wish these two young patients every success.

Why Do Cancer Surgeons Cure More Patients Than Medical Oncologists?

Surgery remains the most curative form of cancer treatment. While the reasons for this are many, the most obvious being earlier stage of disease and the better performance status of the patients, there are other factors at work. Surgeons tend to be rugged individualists, prepared to make life and death decisions at a moment’s notice. The surgeon who enters the pelvis expecting an ovarian cyst only to find disseminated ovarian cancer must be prepared to conduct a total hysterectomy and bilateral ovary removal if he/she is to save the patient’s life. It is these types of aggressive interventions that have that revolutionized the treatment of advanced ovarian cancer.

What of the medical oncologists who, with the exception of leukemia and some lymphomas, confront diseases that are difficult to eradicate and for which treatments can be toxic? Trained as incrementalists, they do not expect cures so much as palliation. Their role is not to make hard decisions, but instead to rely upon precedence. Educated in the school of small advances, these physicians are not rewarded for individual successes but they are harshly criticized for any departures from community standards.

Deprived of the opportunity to make bold decisions, medical oncologists follow opinion leaders who instruct them to accrue to standardized protocols. As meaningful advances are few and far between, enormous numbers of patients must be accrued to provide sample sizes with any hope of achieving statistical significance. Among the most disturbing examples of this approach was a trial reported in patients with inoperable pancreatic cancer. The study compared single agent gemcitabine to gemcitabine plus erlotinib. The trial achieved an improvement in survival that led the FDA to approve the two-drug combination. Yet, the actual improvement in median survival was a mere 10 days. The authors beamed, “To our knowledge, this randomized phase III trial is the first to demonstrate statistically significantly improved survival in advanced pancreatic cancer by adding any agent to gemcitabine.” (Moore, MJ et al J Clin Oncol, 2007). To the average observer however, a clinical trial that required 569 patients to improve median survival from 5.91 months to 6.24 months (10 days) would hardly seem cause for celebration.

Medical oncologists have become so accustomed to these marginal advances that they are unmoved to depart from standard protocols lest they be accused of breeching guidelines. This might be acceptable if chemotherapy provided meaningful benefits, but the extremely modest advantages provided by even the best clinical trials scream for medical oncologists to think, well, more like surgeons.

While community oncologists think it heresy to step around a National Comprehensive Cancer Network (NCCN) guideline, investigators at the best institutions, the opinion leaders, have begun to question the merit of blind protocol accrual and come to recognize that many critical questions cannot be easily answered through the current trial process. Questions such as the role of liver resection for colon cancer patients with disease spread to the liver or the role of additional chemotherapy after that liver surgery, simply may not lend themselves to randomized trials. In a review of the topic by one of the leading investigators in the field, Dr. Nancy Kemeny from Memorial Sloan-Kettering in New York examined this dilemma, “The management plan for each patient should be decided by a multidisciplinary team, it may not be possible or ethically defensible to perform large randomized adjuvant trials comparing chemotherapy with surgery alone or comparing modern chemotherapy with older regimens. It may be reasonable to extrapolate from adjuvant trials and meta-analyses showing predominantly disease-free survival benefit. Each decision on postoperative chemotherapy should be viewed in context of prior treatment, surgical preference and individual patient characteristics.”

How refreshing. Finally a clinical investigator has recognized that patients must be managed on an “individual basis” regardless of what the clinical trial data does or does not support.

The concept of personalized medicine flies in the face of contemporary guideline driven treatment. Individualized care is on a collision course with the NCCN. It is time for medical oncologists to reclaim the high ground in doing what is right for patients, using resources that enable them to make smart decisions and to eschew standardized care. In cancer, the dictum “one size fits all” is more accurately “one size fits none.”

Is It Ethical to Deny Cancer Patients Functional Analyses?

The ethical standards that govern human experimentation have become an important topic of discussion. Clinical trials are conducted to resolve medical questions while protecting the rights and well-being of the participants. Human subject committees known as Institutional Review Boards (IRB’s) not only confront questions of protocol design and patient protection but also the appropriateness of the questions to be answered. The Belmont Report (1979) defined three fundamental principles i) respect for persons, ii) beneficence and iii) justice. These have been incorporated into regulatory guidelines codified in the code of federal regulations like 45 CFR 46.111. One historical experience offers an interesting perspective upon contemporary oncologic practice.

With advances in cardiac surgery in the1970s and 1980s, in both valvular and coronary artery bypass, an alarming amount of post-operative bleeding was being observed. To address this complication an enzyme inhibitor named Aprotinin was developed by Bayer pharmaceuticals. The drug works by preventing the body from breaking down blood clots (thrombolysis). This is critical for the prevention of postoperative bleeding. Concerns regarding its safety led to Aprotinin’s temporary withdrawal from the market, but those have been resolved and the drug is again available.

After Aprotinin’s introduction, clinical trials were conducted to test its efficacy. Initial results were highly favorable as the drug consistently reduced post-op bleeding. By December 1991, 455 patients had been evaluated providing strong statistical evidence that Aprotinin reduced bleeding by more than 70 percent. Despite this, trialists continued to accrue patients to Aprotinin versus “no treatment” studies. By December 1992, more than 2,000 patients had been accrued and by October of 1994, the number had increased to more than 3,800 patients. Yet the 75 percent risk reduction remained entirely unchanged. Thus, 3,400 patients at untold cost and hardship were subjected to the risk of bleeding to address a question that had long since been resolved.

In a 2005  analysis, Dean Fergusson et al, decried that it should have been evident to anyone who cared to review the literature that Aprotinin’s efficacy had been established. Further accrual to clinical trials beyond 1991 only exposed patients to unwarranted risk of bleeding, and had no possible chance of further establishing the clinical utility of the intervention. This stands as a striking lack of consideration for patient well-being. Fergusson’s review raises further questions about the ethics of conducting studies to prove already proven points. With this as a backdrop, it is instructive to examine functional profiling for the prediction of response to chemotherapy.

Beginning in 1997, a cumulative meta-analysis of 34 clinical trials (1,280 patients), which correlated drug response with clinical outcome was reported. Drug sensitive patients had a significantly higher objective response rate of 81 percent over the response rate of 13 percent for those found drug resistant (P < 0.0000001). This was met by the ASCO/Blue Cross-Blue Shield Technology Assessment published in Journal of Clinical Oncology (Schrag, D et al J Clin Oncol, 2004) that cried for further clinical trials. A subsequent meta-analysis correlated the outcome of 1929 patients with leukemia and lymphoma against laboratory results and again showed significantly superior outcomes for assay directed therapy (P <0.001) (Bosanquet AG, Proc. Amer Soc Hematology, 2007). In response, a second ASCO Guideline paper was published in 2011. (Burstein H et al J Clin Oncol, 2011) Although the authors were forced to concede the importance of the field, they concluded that “participation in clinical trials evaluating these technologies remains a priority.” Most recently we conducted a cumulative meta-analysis of 2581 treated patients that established that patients who receive laboratory “sensitive” drugs are 2.04 fold more likely to respond (p < 0.001) and 1.4 fold more likely to survive one year or more (p <0.02) (Apfel C. Proc Am Soc Clin Oncol 2013).

Slide Detail-smallEach successive meta-analysis has concluded, beyond a shadow of a doubt, that human tumor functional analyses (e.g. EVA-PCD) identify effective drugs and eliminate ineffective drugs better than any other tool at the disposal of cancer physicians today. Not unlike those investigators who continued to accrue patients to trials testing Aprotinin, long after the result were in, oncologists today continue to clamor for trials to prove something which, to the dispassionate observer, is already patently obvious. If we now pose the question “Is it ethical to deny patients functional analyses to select chemotherapy?” the answer is a resounding No!

Triple Negative Breast Cancer: Worse or Just Different?

The term “triple negative breast cancer” (TNBC) is applied to a subtype of breast cancers that do not express the estrogen or progesterone receptors. Nor do they overexpress the HER2 gene. This disease constitutes 15 – 20 percent of all breast cancers and has a predisposition for younger women, particularly those of black and Hispanic origin. This disease may becoming more common; although, this could reflect the greater awareness and recognition of this disease as a distinct biological entity.

On molecular profiling, TNBC has distinct features on heat maps. The usual hormone response elements are deficient, while a number of proliferation markers are upregulated.  Not surprisingly, this disease does not respond to the usual forms of therapy like Tamoxifen and the other selective estrogen response modifiers known as SERMs. Nonetheless, TNBC can be quite sensitive to cytotoxic chemotherapy. Indeed, the responsiveness to chemotherapy can provide these patients with complete remissions. Unfortunately, the disease can recur. Complete remission maintained over the first three to five years is associated with a favorable prognosis, with recurrence rates diminishing over time and late recurrences more often seen in estrogen receptor-positive cancers.

Triple negative breast cancer is not one, but many diseases.

MTOR-pathway-ger Among the subtypes are those that respond to metabolic inhibitors such as the PI3K and mTOR directed drugs. Another subset may respond to drugs that target epidermal growth factor. There are basal-types that may be somewhat more refractory to therapy, while a subset may have biology related to the BRCA mutants, characterized by DNA repair deficiencies and exquisite sensitivity to Cisplatin-based therapies. Finally, a last group is associated with androgen signaling and may respond to drugs that target the androgen receptor.

Some years ago, we used the EVA-PCD platform to study refractory patients with breast cancer and identified exquisite sensitivity to the combination of Cisplatin plus Gemcitabine in this patient group. We published our observations in the Journal of Clinical Oncology and the combination of Cisplatin or Carboplatin plus Gemcitabine has become an established part of the armamentarium in these patients.

The I-SPY-2 trial has now used genomic analyses confirming our observations for the role of platins in TNBC. This iSignal_transduction_pathways.svgn part reflects the DNA repair deficiency subtype associated with the BRCA-like biology. More recently, we have examined TNBC patients for their sensitivity to novel therapeutic interventions. Among them, the PI3K and mTOR inhibitors, as well as the glucose metabolism pathway inhibitors like Metformin. Additional classes of drugs that are revealing activity are the cyclin-dependent kinase inhibitors, some of which are moving forward through clinical trials.

One feature of triple negative breast cancer is avid uptake on PET scan. This reflects, in part, the proliferation rate of these tumors, but may also reflect metabolic changes associated with altered glucose metabolism. In this regard, the use of drugs that change mitochondrial function may be particularly active. Metformin, a member of the biguanide family influences mitochondrial metabolism at the level of AMP kinase. The activity of Metformin and related classes of drugs in triple negative breast cancer is a fertile area of investigation that we and others are pursuing.

When we examine the good response of many triple negative breast cancers to appropriately selected therapies, the potential for durable complete remissions and the distinctly different biology that TNBC represents, the question arises whether TNBC is actually a worse diagnosis, or simply a different entity that requires different thinking. We have been very impressed by the good outcome of some of our triple negative breast cancer patients and believe this a very fertile area for additional investigation

Mammography – The Evolving Story of a Diagnostic Tool

The use of low-dose radiation to detect occult breast malignancies can be traced to work done at the MD Anderson Cancer Center in the 1950s. Early published studies conducted by the “Egan technique,” correctly identified the majority of palpable cancers subsequently proven malignant at the time of surgery. As a diagnostic tool, mammography is an effective means of confirming the presence, and defining the extent, of breast pathology in woman at high risk for cancer, or who note a pamammogramslpable lump. No one is arguing the diagnostic use of this technique. Where the controversy has arisen over the last years is the use of mammography as a screening technique.

To clarify the use of terminology, screening techniques are applied to the general population to identify unrecognized disease. The popularity of mammography as a screening technique led to the recommendation that every woman over 40 should have an annual mammogram. The problem with screening techniques is that they apply a diagnostic tool to a population at low risk. This burdens the technology with numerous false positives, engendering  costs, risks, and toxicity for those who undergo unnecessary biopsies and surgery. The entire discussion came into sharper focus in the past week with the publication of a large Canadian study that examined the impact of mammographic screening over a 25-year follow up in women ages 40-59.

In this study, launched in 1980, more than 89,000 women were divided into two groups. One group underwent routine physical examination and the second group had routine physical examination combined with mammogram. There were 3,250 diagnoses of cancer in the 44,925 women who underwent mammography and 3,133 cancers diagnosed in the 44,910 women who underwent physical examination alone. Five hundred patients in the mammography group and 505 women in the control group died of their disease. While women who had mammograms were more likely to be diagnosed with breast cancer, this did not have an impact on their risk of dying from the disease. Furthermore, 22 percent of women with positive mammograms did not have cancer at definitive workup. The conclusion of paper and the accompanying editorial by Mette Kalager from Oslo, Norway, was that ”the rationale for screening by mammography needed to be urgently reassessed.”

What are the shortcomings of the study? Mammographers have claimed that the equipment used was suboptimal, leading to less sensitive detection that might have occurred with modern, high-quality digital equipment. There was also no group over 60. It is also theoretically possible that some patients obtained mammography after concluding the study, or had mammograms done during the study, contaminating the final results. Nonetheless, this is a high quality randomized study in a large population that fails to provide an impact upon survival for a widely used technique.

Prior meta-analyses conducted between the 1960s and 1980s revealed a reduction in deaths in breast cancer between 15 percent and 25 percent in the population of women age 50 to 69. Explanations for the disparity between the current study and those older studies may include the relative lack of sophistication of the population during the 1960s through 1980s, who might fail to evaluate a breast lump, thus, earlier detection would have a significant impact on those not responding to even physical evidence of disease.

A second confounding variable is the broad use of Tamoxifen, which has so profoundly influenced the natural history of breast cancer, that the earlier detection of breast cancer may be less important than the potent efficacy of anti-hormonal agents. This is an interesting wrinkle in the story, as it is contrary to most contemporary thinking that holds that early detection, not treatment is the principal influence upon better outcomes today.

So where does this study leave us?  There are several points that must be considered. The first is that mammography is a test not a treatment. Tests perform according to their performance characteristics, described as “sensitivity and specificity.” Within this framework mammograms are sensitive and specific enough to provide immense value ….in the right patient population, e.g. those at some risk for the disease in question. How you define that “risk” is the rub.

Mammograms identify the disease; they do not influence its biology. While some may demand that more sensitive equipment for the detection of disease be implemented, a different principle may underlie the findings. This would be that cancer, at virtually any stage of diagnosis, is a systemic disease with its own trajectory. Under this scenario, mammograms in an unselected population provide little more than a lead-time bias. This term is applied when a test identifies an event earlier than it might have been found, but has no impact on the ultimate outcome. Lead-time bias is a common phenomenon in screening techniques and has been the rallying cry for those who argue against PSA screening for men. Once again, the number of patients diagnosed versus the number of patients requiring intervention is the overarching dilemma.

While we seek to decipher the genetic basis of cancer using increasingly sophisticated genomic techniques, we recognize that cancer is common and that a substantial percentage of patients may not die of their disease. Cancer results from stresses that force cells to either die or seek novel mechanisms to survive. Deprived of estrogen, testosterone, nutrients, oxygen or growth factors, cells within the aging human body discover novel ways to stay alive, albeit to the detriment of the organism as a whole. However humbling, it can be argued, that it is pathways that aberrant cells pursue that guides the trajectory of the disease, largely independent of our roles as diagnosticians and treating physicians.

Barretos Cancer Center of Brazil – The Asymmetric War On Cancer

Barretos logoI recently returned from a lecture tour at the Barretos Cancer Center of Brazil located 300 miles from Sao Paulo. This cancer center, founded in 1968, has become one of the world’s leading programs for the diagnosis and treatment of malignant disorders. Before this small town became famous for cancer care, however, it was a recognized site for rodeos. The city of Barretos sits in the middle of Brazil’s agricultural region with sugar cane and cattle the principal industries. The hospital itself is a charity where all care is delivered free of charge. Patients from all over the country arrive by bus and ambulance to undergo high-level diagnostic, surgical and medical treatment. Much of the funding comes from the government, but a large amount of the money comes from charitable donations in the form of cattle that are auctioned off to provide money. In addition, donations from the leading musicians of the nation, including Michel Telo, help in the fundraising efforts.

We arrived at Ribeiro Preto airport where we were met by a driver who brought us the 1-1/2 hour trip to Barretos. I was accompanied by a reconstructive plastic surgeon who was donating a month of her time to the Barretos program. The following morning, the director of the program, Dr. Andre Lopes Carvalho, brought me to the hospital for the lecture. The audience consisted of MDs and MD/PhDs, with many scientists and technical staff. It was well received and followed by a small coffee reception.

From there, the Director of Molecular Biology and the Chief of Pathology gave me a tour of the facility. There, in the center of Brazil was a sophisticated research institution with every capability. DNA sequencing performed on Illumina and Ion Torrent equipment. In a tour of the pathology department I was shown archived blocks from tens of thousands of cancer patients, all maintained in a central repository. My discussion with the Chief of Pathology, Dr. Cristovam Scapulatempo-Neto, was most instructive.

It must be remembered that Brazil is a nation of stark contrasts, on the one hand, abject poverty and on the other, extreme wealth. The dilemma for the medical system is to deliver care that meets the needs of the greatest number of patients at the lowest possible cost. Dr. Scapulatempo-Neto confronts an almost impossible dilemma. He cannot possibly afford the companion diagnostics so common in America, which match patients to the drugs of interest under FDA regulation, like the COBAS BRAF mutation test for Vemurafenib or the VYSIS ALK Break Apart FISH probe for Crizotinib. At several thousand dollars per test, these tests are beyond the reach of the Brazilian system. More to the point, many of the drugs are not covered by the national insurance.

To address the need, this physician has redoubled his efforts in immunohistochemistry. This technique uses special stains and antibodies to measure the presence or absence of proteins. Unlike DNA tests, which identify amplifications and mutations, immunohistochemistry identifies the end-product, the business end of cancer abnormalities. I was amazed by the accuracy and affordability of these increasingly sophisticated IHC tests. While a COBAS or VYSIS test might run thousands, he can conduct high quality IHC for 100 dollars. With a medical center that sees 10,000 new cancer patients per year, the cost savings are significant.

I realized that this was indeed an asymmetric war on cancer; low tech answers to high tech problems. I became increasingly enthusiastic about the prospect of utilizing our EVA-PCD platform in this population. After all, these medically indigent patients are barely able to receive even standard cytotoxic chemotherapies, only generic drugs, and very few newer classes of agents are available. The cost saving associated with doubling responses and restricting futile care could be enormous. While gene sequencing technologies become faster, better, and less expensive, the information that they provide for most common malignancies remains to be determined. A practical, comparatively inexpensive tissue culture platform capable of testing both cytotoxic drugs and targeted agents would be a remarkable step forward for the population in Brazil. It is my hope to collaborate with this group and bring our technology to the Brazilian population.

In Cancer – If It Seems Too Good to Be True, It Probably Is

The panoply of genomic tests that have become available for the selection of chemotherapy drugs and targeted agents continues to grow. Laboratories across the United States are using gene platforms to assess what they believe to be driver mutations and then identify potential treatments.

Among the earliest entrants into the field and one of the largest groups, offers a service that examines patient’s tumors for both traditional chemotherapy and targeted agents. This lab service was aggressively marketed under the claim that it was “evidence-based.” A closer examination of the “evidence” however, revealed tangential references and cell-line data but little if any prospective clinical outcomes and positive and negative predictive accuracies.

I have observed this group over the last several years and have been underwhelmed by the predictive validity of their methodologies. Dazzled by the science however, clinical oncologists began sending samples in droves, incurring high costs for these laboratory services of questionable utility.

In an earlier blog, I had described some of the problems associated with these broad brush genomic analyses. Among the greatest shortcomings are Type 1 errors.  These are the identification of the signals (or analytes) that may not predict a given outcome. They occur as signal-to-noise ratios become increasingly unfavorable when large unsupervised data sets are distilled down to recommendations, without anyone taking the time to prospectively correlate those predictions with patient outcomes.

Few of these companies have actually conducted trials to prove their predictive values. This did not prevent these laboratories from offering their “evidence-based” results.

In April of 2013, the federal government indicted the largest purveyor of these techniques.  While the court case goes forward, it is not surprising that aggressively marketed, yet clinically unsubstantiated methodologies ran afoul of legal standards.

A friend and former professor at Harvard Business School once told me that there are two reasons why start-ups fail.  The first are those companies that “can do it, but can’t sell it.”  The other types are companies that “can sell it, but can’t do it.”  It seems that in the field of cancer molecular biology, companies that can sell it, but can’t do it, are on the march.

Cancer Patients Take Heart: The Power of Public Opinion

A January 27, 2014, report on National Public Radio brought recent discussions into sharper focus. Though the story was unrelated to cancer, the lessons learned provide a road map for cancer patients in their pursuit of the most effective, least toxic treatments.

The condition known as “clubfoot” (talipes equinovarus) is a congenital deformity that afflicts one of every 1,000 births in the US. The abnormal internal rotation of the ankle is highly debilitating if not corrected shortly after birth. For decades, orthopedic surgeons used complex surgical procedures that disrupted the ankle structure and realigned the bones. Despite numerous surgeries, this rarely corrected the deformity resulting in chronic arthritis and gait disturbances. The costs were significant and the loss of productivity for those afflicted even greater, yet the dilemma remained unresolved.

PonsetiInto the fray came Dr. Ignacio Ponseti. Ponseti, the son of a Spanish watchmaker, had gained a unique perspective on structural integrity working in his father’s shop. Fleeing the Spanish Civil War he came to the US to practice orthopedic surgery at the University of Iowa. Recognizing the poor outcomes for clubfoot surgery, he took it upon himself to rethink the problem. After all, newborns have flexible ligaments. These ligaments, he reasoned, could be re-trained through a series of casts that were replaced serially over months after birth. Once the foot was in better alignment, the children were placed in a boot to retrain the joint into its normal alignment. Not surprisingly, this simple, noninvasive, inexpensive method was eschewed by the orthopedic professionals. Undaunted, he continued to practice his art, with excellent results year after year. Dr. John Herzenberg, a Baltimore-based practitioner of the Ponseti method was quoted: “People were falling over themselves to do fancy invasive surgery, and this one strange old guy, who speaks softly with a Spanish accent in Iowa, was getting sort of ignored by the drumbeat of people who were in favor of surgery.” Despite its obvious appeal and its manifest successes, this technique remained largely in Iowa for 50 years.

And then came the Internet. When a child born with clubfoot in 2000 was recommended for standard surgery, her mother went online to examine all the options and came across Dr. Ponseti. She traveled to Iowa for an opinion. Convinced that Dr. Ponseti’s approach was superior, this brave mother took the leap and undertook the Ponseti method. Dr. Ponseti completely corrected the child’s foot. Horrified that her daughter would have suffered a life of misery without this brilliant breakthrough, this young mother took it upon herself to get the word out. Using the Internet, she created a Yahoo Support Group called “No Surgery 4 Clubfoot.”  Families with afflicted children could now find out about this technique and identify practitioners who used it.

Voting with their feet, parents took their children to centers that applied this simple, relatively noninvasive approach. Over time, the academic community and their adherents to invasive surgery found themselves on the wrong side of patient referrals. Demanding better outcomes for their children, parents charted a new course for their medical care and forced their doctors to agree or be left behind. With a 97% success rate today, virtually every orthopedic surgeon in America practices the Ponseti method. Indeed, it is now recommended by the American Academy of Orthopedic Surgeons.

I relate this story to cancer patients as they confront similar resistance. While marginally effective therapies are promoted by many academic centers, simple, comparatively easy techniques are available that can empower patients in treatment selection. Just like the clubfoot parents, cancer patients must demand access to treatment options and explore every lead.

The Internet has offered an entirely new platform for cancer patients to communicate their experiences, recommend physicians, educate friends and family members and change referral patterns. The power to change the way cancer is treated in America today is within the grasp of the patients themselves. Just like Dr. Ponseti, who knew that his method worked and just like his patients who avoided the pain and suffering they would have otherwise endured, patients enlightened about better ways to treat cancer need to communicate and take charge of their disease.

Rallying the Troops to Confront Cancer

The recent blog “Stand Up To Cancer Research!” described some of the pitfalls of modern cancer research and the clinical trial process. It has engendered an active discussion. It may be helpful to address some of issues raised. For those of you who did not have the opportunity to read that blog, it defined the difficulty that many patients encounter when they seek experimental treatments. Clinical trials are often only available at select centers, sometimes at great distances from patient’s homes. There can be rigid inclusionary and exclusionary criteria, and the pre-entry evaluations e.g. re-biopsy, CT/PET, etc. can be daunting, time consuming and inconvenient. Travel and accommodations may come at great personal expense.

I penned the blog, in part, to remind patients that they are ultimately in control of the process. One patient asked how can “we stand up to the system” describing herself a consumer while “they’ve got the goods.” This is the frustration many people feel. It should be remembered, however, that a substantial portion of research support comes from tax dollars and charitable donations. These are your dollars. If the system is not working, then those responsible must be held accountable. The American public has the power of the vote. Patient advocates can approach and lobby their representatives and demand improvements in the clinical trial process. To wit, the level of scrutiny and restriction upon access to new drugs must be re-examined. There is an army of well-trained clinical oncologists capable of delivering experimental drugs today. Not just the fully vetted, just-about-ready-for-prime-time agents currently found in phase III trials, but the really new exciting drugs. Once a drug has passed Phase I and found to be safe in patients, open up the accrual process. “Compassionate use” has virtually disappeared from the lexicon of cancer research. Twenty years ago I made a discovery in the laboratory. Working with the pharmaceutical company and the FDA, we were almost immediately granted access to a yet-to-be approved agent. The combination proved so effective that today it is one of the most widely used regimens in the world. That would not happen today. We simply cannot get access to the best drugs for our patients.

Microscope Detail2-lo resWith the industrialization of medical care, growth of mega-medical systems and the increasing role of government, medicine must be viewed through a different lens. Changes in cancer research will require changes in cancer policy, and policy comes from political power. Cancer patients will need to identify legitimate spokespeople to take their concerns forward to their elected officials. While the current clinical trial process slowly grinds out new development, even the smartest, fastest trials take years to change practice. Every day, more than 1,500 cancer patients die in the United States alone. Cancer patients do not have time for clever doctors to pose interesting questions while they suffer the slings and arrows of ignoble, ineffective therapy. It is time for a change in cancer research, and patients must be the instrument for that change.

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