Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

How to Treat Metastatic Colorectal Cancer

Bassel El-Rayes, MD, Professor and Vice Chair for Clinical Research, Department of Hematology and Medical Oncology, Associate Director for Clinical Research, and Director of the Gastrointestinal Oncology Program Winship Cancer Institute of Emory University

Q: You have just received a new patient, referred to you from Macon, GA. She is a 52-year-old white woman in good general health who is 3 months post op from a left hemicolectomy for a grade 3 adenocarcinoma with extension through muscle but not through the serosa. Three of 15 lymph nodes were positive for cancer. She did not receive post-op radiation or chemotherapy. No molecular testing of the tumor was performed. She now presents with a single 3 cm mass in the liver discovered by CT scan. How will you manage her care?

A: (2016) This 52-year-old patient presents with a solitary liver lesion 3 months after resection of a stage III colon primary. If all her other staging is negative, my first question is do we proceed directly to surgery or should we try chemotherapy first? The short interval between the original cancer and the recurrence makes the case for using chemotherapy upfront followed by surgery. FOLFOX would be the chemotherapy of choice. The biologic agent may be influenced by the molecular profile of the tumor specifically RAS mutational status and MSI. Furthermore, knowing the BRAF mutational status may provide valuable information regarding prognosis. For these reasons, I would obtain a genomic profiling of the tumor. I would administer 2 to 3 months of chemotherapy and then obtain re-staging scans. My overall objective would be to complete roughly 6 months of therapy and follow that by surgical resection or ablation of the liver lesion.
A: (2017) The starting point for the management of this patient is to decide whether to do surgical resection only or to use surgery plus systemic therapy. Given she had initially stage III disease and did not receive adjuvant therapy and the short time interval between resection and recurrence, my preference would be to consider systemic therapy. The second question is about the sequencing of therapies. My preference is to do the chemotherapy first since this will allow for evaluation of responsiveness to therapy. The third question: what type of systemic therapy? This decision is driven by the clinical presentation (left versus right side), molecular profile specifically MSI, extended RAS and BRAF, as well as overall health of the patient. For the right-sided tumors, there is now sufficient data to recommend using bevacizumab in combination with chemotherapy as front-line agent. In the left-sided tumors, there are more options for the biologic agent including bevacizumab or an EGFR inhibitor in the extended RAS wild type. In the mutated RAS, the main option is still bevacizumab. In the MSI-high tumors, consideration of PD-1 antibody without chemotherapy is warranted although data for use of a checkpoint inhibitor in the frontline setting is still limited. The last question is related to the duration of therapy. With the recently presented data in the adjuvant setting showing the relatively small benefit for 6 months over 3 months, I would lean towards giving only 3 months of therapy in this case prior to proceeding to surgery.
Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

You, Me, and 23: DTC Gene Tests

Melinda Roberts, Web and Product Development Lead Globiana Inc.

Q: Many people are interested in their own genes and wonder whether they are predisposed to cancer or other maladies.  You recently participated in the “23 and me” testing process. As a well-educated and informed consumer, did you find that service useful? Were the explanations given sufficient? Was it worth the cost and trouble? Have the results changed anything about your life?

A: Last December, my septuagenarian uncle left an urgent voice message for me, setting off several days of phone tag. When we finally connected he asked, “Have you heard of those DNA-based ancestry services? I know you’ve been researching our family tree, so I thought, why not? I did one and found out that we aren’t even Scottish! We’re Irish! My whole life has been a lie!”
The Pulpit Rock
Grandpa Tam
I thought of all the time I spent tracing some ancestors to the year 1639 and being frustrated that I couldn’t get more than a hundred years on the paternal side. At least we had documents! I looked at the ship’s manifest marking my grandparents’ emigration from Scotland, our family coat of arms that inspired one son’s semester art project, a photo of my Glaswegian grandfather posing proudly in the Shotts and Dykehead Caledonia Pipe Band in East Calder, and thought, “Well, shoot. I’m going to have to spit in a tube.”

Off to 23andMe.com. I had, of course, heard of these services but thought them cost-prohibitive in light of our richly documented heritage, but now I was a little peeved and suddenly $99 was just fine. In fact, I would go one further and spring for the $199 “Health and Ancestry Service” that promised a comprehensive understanding of my ancestry, traits, and health. What a steal.
Just this month my reports were ready, and they were voluminous. Ancestry: 5 reports. Carrier Status: 42 reports. Genetic Health Risk: 4 reports. Traits: 19 reports (What??). Wellness: 8 Reports, plus an invitation to participate in their “DNA Relatives” program and to continue to share and compare information. They even worked in a little gamification, awarding “insights” for each set of research questions answered. 77 reports worked out to $2.58 a report. This was more than a steal.
What I learned:

  • No variant detected for any of the 42 carrier status listed
  • No variants detected for Late-onset Alzheimer’s Disease (you’re welcome, kids), Parkinson’s disease, or Hereditary Thrombophilia
  • Variant detected for Alpha-1 Anti…Antitryp…Antitrypsin Deficiency, but not likely at risk
  • I can detect Asparagus in urine
  • I probably don’t have dimples (I do), or a cleft chin
  • I probably DO have detached earlobes (check), light freckling (check), wet earwax (I have nothing to compare it to, so likely check), lighter eyes (check) had little baby hair (check), a longer second toe (check), no widow’s peak (check), little or no unibrow (check, thanks to tweezing), and prefer sweet taste over bitter (check), am predisposed to weigh more than average (thanks), unlikely to flush with alcohol (how can I tell? I’m probably drunk), likely to be a deep sleeper (check, until firstborn arrived), and don’t move around much in sleep (if I did, my husband and I would have to sleep in the Coliseum)
  • I have 1,258 relatives already in the 23andMe DNA Family! (Good upsell)

The service provides lots of fun graphics, such as the locations of my DNA relatives and migrations of my maternal line (presumably because the guys never asked for directions). Mom, you swung way east before heading north (the shortest route). Good job.

I can’t say I’ve changed anything in my life as a result of these findings, but I am very pleased to be able to tell my children that we are unlikely to face several very traumatic future ailments, and am newly motivated to contribute to their research.
By the way, I am 63% British and Irish. And as I was warned, nothing about Scotland, but of course that is because “Scottish” falls under British. I won’t tell Uncle Dougal.

Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

Leading Retractions in the Cancer Research Literature



Ivan Oransky, MD, is co-founder of Retraction Watch. Oransky is Distinguished Writer In Residence at New York University’s Arthur Carter Journalism Institute, and editor at large of MedPage Today. Adam Marcus is also co-founder of Retraction Watch. Oransky is Distinguished Writer In Residence at New York University’s Arthur Carter Journalism Institute, and managing editor of Gastroenterology & Endoscopy News.

Q: You founded “Retraction Watch” in 2010. It has flourished and filled a substantial niche. In your view, what are the most important retractions or corrections in the cancer literature to date?

A: Without passing judgment on the integrity of cancer research broadly speaking, we have indeed seen several significant cases involving retractions in this field.
Topping the list almost certainly is Anil Potti, formerly of Duke University, whose promising work in oncogenomics – using genetic information to fine-tune chemotherapy – proved to be largely fabricated. Potti’s misconduct helped trigger at least a dozen now-settled lawsuits brought by patients against Duke, and lead to the retraction of 11 papers on which he was a co-author.
Although Duke cut ties with Potti in 2010, the same cannot be said for The Ohio State University and one of its star oncology researchers, Carlo Croce. Croce, chair of the department of cancer biology and genetics at Ohio State, has been under a cloud of suspicion at the institution at various times since the 1990s, but never sanctioned. Although he has at least six retractions to his name, and more than 20 publications with corrections, expressions of concern and other red flags, he has managed to survive several misconduct investigations. He even won a major award this year. One of Croce’s frequent co-authors, Alfredo Fusco, of Naples, Italy, is also on shaky ground. Fusco has lost nine papers to retraction and was under criminal investigation in 2012 for manipulating images in articles and grant applications. According to Nature, Fusco is believed to have employed the services of a professional photography firm to help him prepare his figures.
Even some of the world’s leading oncology researchers have been caught up in misconduct scandals, although not always of their own making. Robert Weinberg of MIT, for example, has had four articles retracted because a former student of his, Scott Valastyan, appears to have improperly reported the data in the studies. (Weinberg has a fifth retraction, of a 2003 paper in Cancer Cell, that did not include Valastyan.)
And Bharat Aggarwal, another highly cited cancer researcher, formerly of the MD Anderson Cancer Center in Houston, has 18 retractions, earning him a spot, at the time of this writing, on our leaderboard.
For sheer volume, we have to single out the recent misfortune at Tumor Biology. The journal was forced to retract 107 papers at a single go after editors learned that they had been victimized in a peer-review scam. (The journal purged 25 articles last year for related reasons.) The authors of the tainted studies all appeared to be based in China. Many of them provided the journal with the names of real scientists but used bogus email addresses that they controlled. Others are believed to have worked with third parties in China that facilitate the publishing of scientific papers.
To anticipate a typical query: Whether cancer research has a higher rate of retraction than other fields is unclear, partly because much research into basic cancer biology is categorized into various areas so the denominator is vague. But we hope our retraction database — still in formation at the time of this writing — will help answer questions like these.
Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

Treating Metastatic Malignant Melanoma, March 2016 vs April 2017

Keith Flaherty, MD, Associate Professor of Medicine, Harvard Medical School; Director of Developmental Therapeutics, Cancer Center, Massachusetts General Hospital

Q: A lot has happened in the field of Metastatic Melanoma since March, 2016. In April of 2017, would your reply be any different? If so, in what way, and why?
A: The only change from 2016 to 2017 in terms of treatment options for a young patient with metastatic disease is that the 2016 leaning toward combination CTLA-4/PD1 immunotherapy has come back to PD1 monotherapy versus BRAF/MEK combination therapy. With two-year follow-up data from the BMS 067 trial, there was very little difference in survival (5%) versus the very large difference in risk of severe toxicity. But, PD1 antibody therapy with CTLA-4 antibody therapy as a backup remains a very compelling option for BRAF wild-type patients and BRAF/MEK combination therapy as a first-line or second line therapy for those with a BRAF mutation remains on the menu.

Response from March 2016

Q: What is your basic approach to handling a new young adult patient in good general health who is referred to you with a diagnosis of Malignant Melanoma, metastatic to liver or lung? The primary cutaneous melanoma, 1.5 mm in thickness, was diagnosed in Maine 5 years ago and was of skin on the forearm; treated there by wide resection with clear margins and no lymph node dissection. There was no molecular/genomic testing of the primary.
A: In a case like this, there are a few additional elements of data that I always try to obtain:

  1. Brain MRI
  2. Serum LDH
  3. V600 BRAF mutation status (younger patients are significantly more likely than older patients to have a V600 BRAF mutation), so it’s likely that this patient has one
  4. Presence or absence of disease-related symptoms
  5. Prior scans that might allow the pace of disease progression to be ascertained (not always possible in a very recently diagnosed patient; but even if 4-6 weeks have passed since the first assessment prior to me seeing the patient, I’ll consider repeating imaging of the lungs and liver to glean the pace of progression.

The factors above go into determining disease burden and pace of disease progression. Presence of brain metastases does not necessarily impact choice of first-line systemic therapy, but certainly informs the need for resection (for single large metastases) or stereotactic radiation for one or several small metastases in parallel with pursuing systemic therapy. The presence of numerous brain metastases would push me to select BRAF/MEK combination therapy if a V600 BRAF mutation were found. Elevated serum LDH, the presence of disease-related symptoms, or evidence of rapid disease progression each push me toward considering of BRAF/MEK combination therapy (presuming BRAF mutant), and certainly two or three of these three factors would force that decision. In the absence of any of these factors, first-line immunotherapy is generally my approach. For most patients that means single-agent PD-1 antibody therapy. But, for young patients who are not deterred by a high rate of severe toxicity and for patients with any of the three “aggressive’ disease warning signs indicated above, I would favor combined CTLA-4/PD-1 antibody therapy. This is based on the higher initial response-rate and short-term ability to control the disease with the combination compared to PD-1 antibody monotherapy. We do not yet know that this combination improves overall survival compared to sequential therapy with PD-1, CTLA-4 and/or BRAF/MEK inhibition. In the absence of that data, I favor PD-1 monotherapy first-line for most patients. If a patient progresses on first-line PD-1 antibody therapy, then I reassess the same warning sign factors as above, now informed by the rate of progression evident on follow-up scans. Modest evidence of progression pushes me to consider CTLA-4 antibody therapy as the second-line approach versus BRAF/MEK combination therapy for more aggressive evidence of disease progression. Recent evidence that the same strategy will soon be an option with MEK inhibitor monotherapy in NRAS mutant melanoma patients. These decision points for selecting first, second and even third line therapy are currently informed by clinical factors. However, we know that each treatment approach can produce years-long remissions as first-line treatment. Thus, it is imperative that we continue to conduct clinical research to develop additional diagnostic methods for identifying those patients predicted to achieve long-term benefit from each of therapies and relay on these for navigating among these multiple treatment options.

Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

Is the PBM Now Your Doctor?


Charles Bennett, MD, PhD, MPP, Smart State and Frank P and Jose M Fletcher Chair, Medication Safety and Efficacy, Smart State Center of Economic Excellence, University of South Carolina and the Hollings National Cancer Institute Designated Cancer Center of the Medical University of South Carolina, Charleston, South Carolina. William Hrushesky, MD, FACP, Founder and Chief Scientific Officer Rythmalytics LLC (Cicada Circadian Coach), West Orange NJ; Chief Medical Officer Ambulatory Monitoring Inc., Ardsley, NY.

Q: Prescription drugs are a big ticket item in American Money Driven Medicine. Since the initiation of pharmacy benefits management (PBM) in 1968, the growth and proliferation of functions of this “middle-man managed care” concept has been so successful that PBMs now control not only pricing, discounts, and drug selection for >250 million Americans, they threaten to become “the prescriber.” Is this a good thing?
A: You and I naively imagine that medical care responsibility logically devolves to the doctor who cares for the patient, diagnoses their condition, and provides accountability for management, treatment, and outcomes. Guess again. Since medicines have grown in cost and costs continue to skyrocket, profit-oriented businesses have muscled the patient and the doctor out of the way. Pharmacy Benefit Manager (PBM)’s plans now replace physician choice in many settings, and if the physician’s choice is expensive, they replace it with less expensive alternatives. These PBMs then profit from the resultant savings.
What is a Pharmacy Benefit Manager (PBM) and how did they get here? PBMs were developed to act on behalf of insurance carriers, self-insured employer plans, Medicare Part D plans, Federal Employees Health Benefits Program, and state government employee plans to maintain or reduce prescription costs while concurrently trying to improve outcomes. These “middle men” corporations are now principal players in our health care system, controlling at least 80% of drug benefits for 260 million Americans.
The initial goals that were instrumental in PBM development seem to have gone astray. The system which put PBMs in place was done with good intentions, but it has now resulted in increased cost to health plans and adverse health outcomes. PBMs restrict access by excluding products from formularies, delaying access through prior authorizations, developing step-by-step care algorithms, defining disparate pricing, and establishing lengthy and complicated paperwork. A recent studyusing Medicare data showed that a switch to a less expensive medication for non-medical reasons, termed as non-medical switching, leads to increased annual medical payments of $6,254 to $13,127 and a higher rate of secondary switching (this time for medical reasons) to another medication. Patient care also suffered.
Anthem health plans’ current $15 billion lawsuit against the PBM Express Scripts seeks to recover rebate funds, and Anthem’s withdrawal from its PBM raised public awareness of the lack of transparency about actual discounted costs of expensive drugs.  Express Scripts is willing to accept Anthem’s withdrawal from their plan and lose 14% in sales revenues, to protect against having to share rebate dollars with health plans and their members. This lack of transparency has recently been addressed by Alan Lyles PhD of the University of Baltimore, College of Public Affairs, who questions PBM value in the healthcare system. Similarly, consumers are suing their insurers for “bait and switch” claims. This action is pressuring states to consider adopting state legislation that limits insurer’s ability to control pharmaceutical formulary decisions.
Traditionally, physicians prescribed medicines that they felt were most likely to help their patients based on clinical judgment rather than cost alone.  PBMs have stepped beyond their historical role and are making formulary decisions that control access to which drugs physicians can prescribe without regulatory oversight or the benefit of clinical experience. What started as a value-based strategy, using clinical guidelines to define a stepwise process of drug selection based on best clinical evidence, yet allowing for individual case decision exceptions, has morphed into blatant cost-based guidelines selecting from a restricted list of drugs to be offered (the formulary) based on the lowest cost and highest profit to the PBM. Lowering pharmaceutical costs in the United States is essential. This must be the purview of professional societies and other healthcare patient and provider groups rather than PBMs profiting directly for every dollar saved.
From a practical perspective of the physician, the laborious prior authorization and step therapy processes used to gatekeep expensive FDA approved drugs are onerous and cost a great deal of time and effort that could be better directed to patient care. This modus operandi also leads directly to inordinately high copays for PBM non-preferred drugs, further influencing decisions without any responsibility or accountability for patient care. Authority without responsibility is an extremely bad practice which will lead to a range of bad outcomes. In essence, the PBM has become the physician without training, knowledge, medical license, or knowledge of the individual and their illnesses.
PBMs have adopted new approaches to control formularies and, thereby drug costs. They remove an existing and generally well-tolerated drug on a formulary and replace it with another less expensive and less validated drug because of better pricing for the new, now “preferred” drug (non-medical switching). This is particularly worrisome for oncology, as biosimilar trastuzumab and biosimilar rituximab are expected to enter the US market soon. It’s possible that PBMs may switch out branded rituximab and trastuzumab despite the absence of a proven 20-year safety history.  Similar concerns apply to persons with a range of complex medical illnesses, such as diabetes. Because of the possible absence of drugs’ proven effectiveness, non-medical switching has potentially important and adverse implications for both the patient and their doctor.
Dr. Elaine Nguyen, a Health Economics and Outcomes Research Fellow at Hartford Hospital, applied macro-analysis to multiple studies looking at the broader implications of non-medical switching on patient clinical and economic outcomes, healthcare utilization, and medication-taking behavior. The study found that non-medical switching is associated with significantly more negative effects upon care than benefits, and negative care effects were even more substantial when non-medical switching occurs among patients who are stable and doing well on their current treatment regimens.
This practice is especially damaging to patients with diabetes, as diabetes is a complex progressive disease. Diabetes requires self-management skills and a positive working doctor-patient relationship. The condition also needs continual fine-tuning of medication, formulation of a diet and exercise regimen, and attending to diabetes-related stress. When non-medical switching is required, it is disruptive to an individual’s current management routine.
The solution to the problem requires a concerted effort among those most impacted (patients and providers), encouragement of conversations, and collaborative problem-solving. Physician and patient groups have begun to work together to voice concerns about PBM practices and to advocate for action. PBMs could help by having a streamlined, universal Prior Authorization process (as supported by the AMA Coalition), publishing coverage policies consistent with the insurer’s medical benefit policies, and providing a list of alternative options when a prescribed option is not available. Coalitions have worked for state legislation to define step therapy and prior authorization but many states still need legislation. Physicians and patients can increase communication with employers, providing details about the impact of their PBM policies on workers. In addition to discussing the interference with disease control and function, the details should also include the topics of worker productivity, absenteeism, and decreased attentiveness when at work to encourage better decision-making when selecting insurers and PBMs. The ultimate goal is to position the physician as the ultimate authority on patient care once again.
As Dr. Seth Baum, CMO of Excel Medical Clinical Trials, eloquently expressed: “What is the cost, and the value, of a life? How do we measure this intangible and all-important metric? I can’t answer this question. I can tell you though that withholding medications from those who might benefit would exact a price I’m unwilling to pay: my personal ethos and professional integrity.”
Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

Preventing Breast Cancer: Research Worth Watching

Susan Love, MD, MBA Chief Visionary Officer, Dr. Susan Love Research Foundation, Encino, CA

Q: The goal of the Dr Susan Love Research Foundation is “…..to find the cause of breast cancer and prevent it now – before it starts”. What are some of the ongoing research studies that are worth watching?

A: Challenging the status quo is part of Dr. Susan Love Research Foundation’s DNA. We are a small nonprofit that seeks to work with the public to conduct, facilitate, and explain research about breast cancer. Working with diverse collaborators such as NASA’s Jet Propulsion Lab and the John Wayne Cancer Center, we extend our ability to focus on innovative research. Our research program is focused on better understanding the human breast to discover why women and some men get cancer. For example, we are working to develop a map of the human breast ducts to facilitate surgery for breast cancer as well as lay the basis for direct delivery of therapy for intraductal disease. Our work on the physiology of the non-lactating ducts suggests that the unit of study is the duct and not the breast, as hormone levels vary duct to duct. We have also begun studies on the microbiome of the breast ductal fluid which suggest the possibility of a protective bacterium.
Recognizing the needs of women in Low- and Middle-Income Countries (LMIC) are different than in western countries, we are developing a self-reading ultrasound to triage palpable breast lumps in collaboration with Clearview Diagnostics and with the support of a National Institutes of Health grant. Most breast cancer in LMICs is premenopausal and presents as a lump and, yet, most lumps in women are benign. This project is being tested in Mexico.
The Foundation is also documenting the collateral damage of breast cancer treatment. This research goes beyond the transient side effects of treatment to the permanent damage that the treatments cause such as “chemobrain” and peripheral neuropathy as well as the psychosocial impact and financial toxicity of breast cancer. We are collecting free-text responses from those living with the disease and analyze what the patients experience, rather than limiting ourselves to standard patient-reported outcome questionnaires. The data was presented at a two-day Think Tank including provider-survivors, people working in the health care delivery system who had also experienced treatment for cancer, and advocates. We are currently working on recommendations from that meeting to improve the delivery of care.
The key to all our research is our unique Army of Women®. The Army is composed of women and men who are willing to participate in research on breast cancer. Researchers submit their projects and, vetting by our Scientific Advisory Board, we eblast them out to the whole army. The Health of Women (HOW) Study™ is a subset of the Army and has several data sets that are used for research.
Our research gives voice to those living with the disease. Central to our goals is translating the science of breast cancer and research to inform and engage the public. We do this through our websiteeducational videos, and the Research Worth Watching blog.
Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

2017 USPSTF on PSA: A Bad Idea


Richard J. Ablin, Ph.D., D.Sc. (hon), Dr. h.c. Professor, Department of Pathology, University of Arizona College of Medicine, The Arizona Cancer Center and BIO5 Institute, Tucson, AZ 85724. Ronald Piana, Freelance Science Writer, Huntington, NY 11743

Q: The new draft USPSTF recommendations for rapid comment on use of PSA for screening represent a big change from 2012. They now read: “The decision about whether to be screened for prostate cancer should be an individual one. The USPSTF recommends that clinicians inform men ages 55 to 69 years about the potential benefits and harms of prostate-specific antigen (PSA)–based screening for prostate cancer” and much more. Shared patient-physician decision making. What do you think? (For last week’s answer to the same question see here)

A: In a troubling reversal of its previous Recommendation against the use of prostate-specific antigen (PSA) screening, the US Preventive Services Task Force has issued a Draft Recommendation that doctors should have a meaningful conversation with male patients between the ages of 55 and 69 about the risks and benefits of undergoing PSA screening. This is a bad public health decision that will only increase the use of an intrinsically flawed test that—as formally noted by the Task Force—does far more harm than good.
Screening to identify preclinical and asymptomatic disease in a population at risk is one of the cornerstones of preventive medicine. However, the success of a screening program depends on the specificity of the test for the disease in question and early identification of these patients must convey a clinical (treatment) advantage. Screening for prostate cancer generally begins with a PSA test, which is specific for a protein in the prostate gland but not for cancer. Moreover, there is no level of PSA diagnostic for prostate cancer; PSA cannot distinguish a harmless, slow-growing cancer from an aggressive one. It’s important to note that prostate cancer is an age-related disease and upward of 80% of men screened will have asymptomatic cancer irrespective of their PSA level, which leads to overdiagnosis and unnecessary treatments that to date have left countless millions of men incontinent and impotent, not to mention the healthcare costs and emotional turmoil that a positive PSA test introduces.
The Task Force’s new Draft Recommendation centers on a doctor-patient informed-decision conversation about PSA screening, across all social and demographic lines. Given the complexity of this issue, it is not feasible for a busy community doctor to elucidate the full spectrum of detailed clinical issues involved in PSA screening.1 Inequities and variability will abound, as is borne out by data. For example, a new study2 that looked at 200,000-plus men found that 37 percent were told only of the advantages of PSA compared with 30 percent who were advised of advantages and disadvantages. More striking, 33 percent were not informed of either. These men were more likely to be Hispanic, not high school graduates, and of low income. Basing a potentially life-changing medical decision on incomplete information will have profound consequences for men across the country.
The Task Force indirectly suggests that doctors and patients should revisit the decision to screen (or not screen) in a Table presented in the Draft Recommendation of estimated effects of PSA-based screening for prostate cancer on men observed in the ERSPC trial. A relevant caveat here3is that the ERSPC trialists have yet to de-identify patient data and make it available for independent review. Without examining individual patient data, it is impossible to confirm any benefit of PSA screening or the validity of the data.
Before the Draft Recommendation goes into effect, doctors across the country need specific guidance from the Task Force on how to conduct informed-decision-making conversations with their patients about PSA testing. It is recommended that the Task Force create a discussion summary similar to the Table included with the Draft Recommendation. Thereby all patients will receive consistent information so that they can make their own assessment of the potential benefits or harms resulting from the PSA test.

References

Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

Big 2017 Change on PSA by USPSTF

Marc B Garnick, MD, Editor in Chief, HMS Annual Report on Prostate Diseases; Gorman Professor of Medicine, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, MA . E. David Crawford, MD, Professor of Urology and Radiation Oncology at The University of Colorado, Anschutz Campus, Aurora, CO; Medical Advisor and Founder, 3DBiopsy, Inc., Aurora, CO

Q: The new draft USPSTF recommendations for rapid comment on use of PSA for screening represent a big change from 2012. They now read: “The decision about whether to be screened for prostate cancer should be an individual one. The USPSTF recommends that clinicians inform men ages 55 to 69 years about the potential benefits and harms of prostate-specific antigen (PSA)–based screening for prostate cancer” and much more. Shared patient-physician decision making. What do you think?

A: The long awaited updated recommendations from the United States Preventive Services Task Force, issued at their traditional 5-year interval, got it right–Again! While the 2012 “D” recommendation from the Task Force was met with great skepticism and animosity from several groups, the change in the 2017 recommendation now emphasizes the importance of the Task Force’s continuing evaluations of new and more mature data.
In a series of four detailed, analytic and erudite publications that provide the underpinnings for their new recommendations, even the most serious students of prostate cancer and prostate cancer screening–ourselves included–can appreciate the enormous task that members of the Task Force and its sub-sections undertook. The result not only justifies the correct C recommendation for those men between ages of 55 and 69 and the unchanged D recommendation for those above 70. Moreover, the recommendation calling for the serious need for more study about the complexities facing men who are at increased risk for prostate cancer– African-American and those with a significant family history–should serve as a call to action for research agencies whose worldwide populations are affected by this common cancer. The complexities of prostate cancer biology are outlined in these accompanying publications and will undoubtedly provide avenues for productive future research programs.
The changes in the Task Force’s recommendations appropriately relied heavily on several key studies- among them, the PLCO, ERSPC and ProtecT. Of the key factors that have become available since issuance of the 2012 “D” guidelines were both the increasing utilization of active surveillance–to help address the issue of over-diagnosis and the harms of overtreatment–and the potential that the development of metastases could be decreased by treatment compared to active maintenance. This latter assessment emanated from the UK ProtecT study and its context must appreciate that many of the patients enrolled in that study who received no active treatment had cancer characteristics such as high Gleason scores that would generally have prompted interventions here in the United States.
In the end, the Task Force has in fact provided a strong rationale for what is commonly happening in practice today despite the universal 2012 “D” recommendations. Patients should consider shared decision making with their health provider about the harms and benefits of undergoing screening, and treatment if a cancer is found, and that values and preferences of the individual patient should play an important role. But, today, as was the case in 2012, the ability to show an overall survival benefit from any screening recommendation still eludes us and the cancer-specific survival benefit, if one exists at all, is at best, very modest. Hopefully, these updated screening guidelines will encourage meaningful research to enable real advances at the patient level to be achieved.
Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

Forget Moonshots: Biomedicine Needs an Air Traffic Control System

Jeff Shrager, PhD, Director of Research, Cancer Commons; Adjunct Professor, Symbolic Systems Program, Stanford University

Q: There never seem to be enough patients matched to cancer clinical trials to quickly test new cancer treatments. Might there be a better way, using new communication technology?

A: Among the few things that everyone can agree upon, one is surely that biomedicine is not an efficient engineering system — that is, a system that efficiently (in time, cost, lives, or whatever else you’d like to measure) reaches its goals to alleviate suffering, etc. When we think of efficient engineering systems, companies such as Apple, Boeing, Google, Tesla, NASA, GE, and Toyota come to mind. Perhaps Big Pharma and parts of the VA and military are efficient engineering systems but surely biomedicine, as a whole, is not.
Granted, biomedicine faces the highly complex problem of matching patients to treatments while at the same time creating and ethically testing novel treatments with budgets that are under constant pressure. But this problem is faced by a huge number of extremely smart people. What is the difficulty? I contend that the difficulty is, in large part, lack of coordination.
When I think of highly efficient coordination, I think of the Air Traffic Control system. The notable pain of air travel notwithstanding, one has to admit that the flight coordination is nearly magical! You can fly from New York to London in 5hrs for $500 while strapped into a 20x200ft aluminum tube (full of explosive fuel) traveling at 500mph, 50,000ft high in an airspace shared with 100,000 other flights doing the same thing in every direction all over the world. And you never think about dying! Well, you may think about it, but realistically you shouldn’t because air travel is spectacularly safe. Instead, worry about escalators and bicycles!
I contend that we can learn from the spectacular success of Air Traffic Control in order to improve biomedicine’s engineering efficiency by improving its coordination. Furthermore, I contend that we can do this without compromising ethics, whilst making everyone involved rich and happy–or at least happy that they are not pissing away money and lives.
Essentially, we have proposed to build a Biomedical Air Traffic Control System that will efficiently search the huge space of plausible treatment regimens, crossed with the relatively small number of available patients in ever diminishing cohorts. I call this approach Global Cumulative Treatment Analysis (GCTA), and we can build it on much more modern technology and with much better understanding of science and engineering than the aviation community had when they built theirs.
GCTA is described in the following video and in more detail in Theoretical Issues for Global Cumulative Treatment Analysis (GCTA).

Cancer Commons is putting together a series of virtual workshops to work out the practical details of GCTA. If you would like to be in the loop for these, please contact me at jshrager@stanford.edu.
Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Back to Full Blog List

Connect With Us

Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

Proposed FDA “Conditional Approval”- More Details


Al Musella, DPM, President, Musella Foundation For Brain Tumor Research & Information, Inc., Hewlett, NY. Marty Tenenbaum, PhD, Founder and Chair, Cancer Commons, Los Altos, CA.

Q: Your April 5, 2017 blog post that proposed a new “Conditional” category for FDA drug approval elicited a number of positive and negative responses. Please explain the proposal in more detail to enable better reader understanding.
A: In Response to “Conditional Approval: Right Solution for the Wrong Problem” by
Shannon Brownlee:
We appreciate Ms. Brownlee’s comments on our recent blog post, but think she missed our key points—perhaps we weren’t clear enough:

  • Conditional approval isn’t intended for cancers that have other options—like some types of breast cancer—but rather for the invariably fatal cancers like glioblastoma multiforme (GBM), for which there aren’t any good FDA-approved options.
  • Conditional approval requires not just evidence of safety, but evidence that the drug has promise, at least in some patients.
  • Using the registry is just a different way of collecting the data that traditionally is collected in clinical trials. Instead of a traditional trial in which only highly selected patients participate and relatively few doctors collect the data, we will be collecting data on the entire range of patients from many doctors.

Having many doctors and patients participate removes a lot of the bias inherent in clinical trials. For example, consider a doctor using an experimental treatment on “thousands” of brain tumor patients in 100 clinical trials in which only a handful of doctors are collecting all of the data. All of the doctors involved have a major financial interest in the outcome. We still have no idea if this treatment helps or hurts—and it has been going on for 40 years. With our system, we would know in a year if it helps or hurts.
Moreover, Ms. Brownlee’s arguments extolling the virtues of randomized clinical trials (RCTs) may reflect an unfamiliarity with the cost-effectiveness of “registry trials,” especially when coupled with modern Bayesian designs.
With the traditional approach, we have been lucky to get 3 or 4 treatments approved in the last 40 years. With our approach, we can expect at least 3–6 new treatments conditionally approved each year, as the cost to get approval would be on the order of 1–2% of the cost using the current traditional approach.

  • As Ms. Brownlee states, “It took more than a decade to accumulate enough patients” in an RCT to demonstrate the ineffectiveness of autologous bone marrow transplant (ABMT) in breast cancer. Further, “A few patients may actually have been helped by the Avastin, but there is no way to predict ahead of time whether patients would be helped or harmed.” These points demonstrate the limitations of classical RCTs versus Bayesian point-of-care trials that can be run on top of a registry.
  • The big challenge and opportunity regarding investigational treatments that show promise in some patients is to identify and continuously refine the cohort for whom an intervention is effective, as efficiently as possible. This requires a Bayesian approach, which can rapidly replicate successes and discard failures, not accruing a large trial to test a specific hypothesis, which is likely to be wrong.
  • A registry that captures biomarkers, treatments, and outcomes from patients undergoing a variety of interventions can provide rigorous cross-controls, which are every bit as valid as those provided by randomization.

Using Ms. Brownlee’s example of ABMT, in our system, the registry would have quickly picked up that it was not as good as standard chemotherapy. The current system allowed 41,000 women to use a treatment whose effectiveness was unknown because nobody was tracking it. An RCT took 10 years to find an answer that our registry may have had in as little as 1 year, saving many lives.
Ms. Brownlee states that the registry can’t show efficacy. We disagree. If you have the majority of patients being tracked in the registry, you can use all of the patients who are NOT taking the treatment as the control group. Comparing to the old historic control is useless for brain cancer—almost everyone died and we did not collect the necessary biomic data to correctly match them with current patients.
The comparison that needs to be made is which of many possible new treatments and combinations works the best. Some patients would probably stick with the old standard of care—we would be encouraging them to participate as well—so we can see if the current standard is better than any of the new treatments.
We are talking about using conditional approval only in cases where there really is no acceptable standard of care. And we ARE looking for new drugs and combinations that have extraordinary power to improve outcomes, not looking for something that extends life by weeks. We agree it wouldn’t make sense in a disease where the standard treatments offer hope.
In summary, our proposal is not to minimize the research, it is to maximize the amount of research done to a drug, just in a different time period—after phase 1 instead of before the end of phase 3.
As to picking up idiosyncratic reactions, by definition, these are rare and do require a large group of patients being tracked to identify how frequently they occur. With our registry, it is simple to analyze the data and get an early warning. Having the genomic data would allow us to try to figure out which patients are most likely to have such a problem. With traditional trials, which usually only allow a select population to be tested, a reaction that only occurs in the elderly or in minorities—which are underrepresented— may never be found. Once a drug is approved and underrepresented groups use it, side effects are not tracked as closely as they would be in our registry.
For more reference, please read “Rapid Learning for Precision Oncology” published in Nature on Jan 21, 2014. We include a free PDF download. Please see below for a 3-minute video showing how the Bayesian approach can be applied to medical research in a new method called Global Cumulative Treatment Analysis (GCTA).


Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.