"" Ralph Moss—Cancer Consultant

Tuesday, November 6, 2018

IMMUNE THERAPY PUTS STAGE IV BREAST CANCER INTO REMISSION

Electron microscopic picture of blood, including lymphocytes

Scientists at the National Cancer Institute (NCI) in Bethesda, Maryland, have reported putting a woman with advanced, stage IV breast cancer into complete remission using an innovative form of immunotherapy.

A team of almost two dozen NCI scientists reported on the case of Judy Perkins, a 49-year-old engineer from Florida who had metastatic breast cancer. Like many patients, her tumor was estrogen receptor-positive and HER2-negative. According to their report in Nature Medicine, the treatment destroyed her cancer cells so effectively that she has been in remission for two years. The NCI doctors who cared for her have called her response “remarkable.” 

The Ultimate Challenge


"My condition deteriorated a lot towards the end," she said, "and I had a tumor pressing on a nerve, which meant I spent my time trying not to move at all to avoid pain shooting down my arm. I had given up fighting,” she told the Guardian. “After the treatment dissolved most of my tumors, I was able to go for a 40-mile hike." She also stated: "I even recently paddled 1,200 miles around the state of Florida by sea kayak as part of the Ultimate Florida Challenge."
Her treatment consisted of removing some of her tumor and also white blood cells that had already infiltrated the area around the cancer cells. These were then programmed to enhance their cancer-killing effects and injected back into the her body. The result was a massive kill-off of cancer cells, with no sign of any remaining malignancy.
Ms. Perkins also received an immune checkpoint inhibitor, pembrolizumab (Keytruda®) but that drug alone does not often result in dramatic regressions in this type of breast cancer.
Of course, it will take a full-scale clinical trial to know how often (if at all) this sort of "miracle" can be reproduced in others. Nonetheless, breakthrough treatments sometimes emerge from single case reports. This remarkable event certainly justifies all the attention that has been paid to cancer  immunotherapy in recent years, including the 2018 Nobel Prize to scientists who first developed immune checkpoint inhibitors.
Interested readers can learn more details on Ms. Perkins's case in the scientific report below:
Link to the original article



Thursday, October 25, 2018

IS GcMAF REALLY SAFE AND EFFECTIVE?



Source: http://gcmaf.timsmithmd.com/book/chapter/65/


GcMAF (also spelled Gc-MAF) is a non-conventional cancer treatment that has gotten a great deal of attention in the past few years. There is no end to conspiracy theories swirling around its discoverer, Nobuto Yamamoto, PhD, and his supposed "breakthrough cancer treatment." 


Interest in GcMAF surged in July 2015, when a doctor who administered the compound, James Jeffrey Bradstreet, MD, was found dead, in the Rocky Broad River in mountainous North Carolina with a bullet wound to the chest. The mainstream media, echoing the police, claimed that he was involved in an "international medical gray market" manufacturing GcMAF, and that as this network began to unravel, "so, too, did Bradstreet’s life," to quote the Washington Post. His family and some patients claimed that Dr. Bradshaw was murdered, probably because of his anti-establishment stance. There are still  unanswered questions concerning Bradshaw's death, but the focus of this blog is on the efficacy of GcMAF.

"Gc" stands for "globulin component" of blood serum, while "MAF" stands for "Macrophage Activating Factor." MAFs occur naturally in the human body. In a 1997 paper, Yamamoto stated that "treatment of human Gc protein with...sialidase [enzyme] generated a remarkably potent MAF, termed...GcMAF."

According to some scientists, MAF has various functions, such as macrophage activation and anti-tumor activity. It thus is part of a larger topic, which is the immunotherapy of cancer.

When Dr. Yamamoto burst on the cancer scene with the announcement of his “cure” for stage IV cancer in 2008 I (like many people) was excited. Yamamoto had been a biological researcher at the Einstein Medical Center in Philadelphia for many years. After his retirement, he founded the Socrates Institute for Therapeutic Immunology to continue his work. But the "Socrates Institute" is a mystery. There is no website for any Socrates Institute in Philadelphia. Its address, 1040 66th Avenue, is an ordinary house in an ordinary neighborhood, presumably Dr. Yamamoto's residence. This organization's tax exempt status was automatically revoked by the IRS for failure to file the requisite forms for three consecutive years. According to Gudiestar.org, "Further investigation and due diligence are warranted."

At the time, I managed with great difficulty to get Dr. Yamamoto on the phone, but although I expressed a willingness to drive from State College to Philadelphia to investigate his treatment, he was unable to meet with me. Even then, he sounded frail and forgetful. (He was born in 1925 and is thus in his 90s.)

The Anticancer Fund authors tried to track down the various contributors to Yamamoto’s papers:

“After months of trying to get additional information on the patients and scientists involved in this research we came to the conclusion that these data should not be relied on since there are important issues in the methodology and procedures. The same group has also presented their results to different scientific conferences and we could confirm that one co-author's participation was denied by the person himself, while we could not contact others besides Nobuto Yamamoto.”
This is all strange and disturbing, especially if one is planning to make life-and-death decisions based on such information. It should be noted that many of the articles claiming that GcMAF is an effective treatment of breast and colorectal cancer have been retracted by the journals in question. In the opinion of the Anticancer Fund authors, 
“GcMAF has not been properly studied in clinical trials and its laboratory results still need to be confirmed independently. So far, all claims on the efficacy of this product have no solid scientific basis.”
This is true. But this is not to say that GcMAF might not turn out to be worthwhile, if future research confirms its value. When we search PubMed for GcMAF and cancer, we come up with 45 articles in the peer-reviewed literature. According to three Iranian doctors, "Such medications show great potential in cancer immunotherapy using natural human mechanisms against neoplasms." Some Japanese scientists have stated, "Macrophage activating factor (MAF)-based immunotherapy has a wide application for use in treating many diseases via macrophage activation." Other than Dr. Yamamoto's withdrawn papers, there are a few case histories in which patients allegedly benefited after being given GcMAF. But they also received other treatments, such as hormonal therapy (for breast cancer) sonodynamic therapy, tumor treating fields, etc. It is always difficult to draw conclusions from such cases.

BOTTOM LINE: The study of GcMAF is a legitimate area for research. It is not intrinsically a fraud or a fake, as some sites have asserted. However, readers should be aware that the claims of GcMAF's efficacy in cancer are very shaky. Also, one generally does not know the origin or true nature of substances sold under this name. Counterfeits abound. Thus taking "GcMAF" is a risky proposition, and harm can come from taking improperly prepared medications. I would not use this as a cancer treatment, especially in lieu of any treatment with a well documented record of beneficial effects.


References:

Miller, Michael E. The mysterious death of a doctor who peddled autism ‘cures’ to thousands. Washington Post, July 16, 2015.

Yamamoto N, Naraparaju VR. Immunotherapy of BALB/c mice bearing Ehrlich ascites tumor with vitamin D-binding protein-derived macrophage activating factor. Cancer Res. 1997 Jun 1;57(11):2187-92.







Friday, October 12, 2018

WILL IMMUNE CHECKPOINT INHIBITORS WORK FOR YOU?



Human lymphocyte, electron micrograph
(Source: Wikimedia Commons)

One of the most important questions about immune checkpoint inhibitor (ICI) therapy is who will respond to this new type of treatment. A recent paper from the University of Texas M.D. Anderson Cancer Center, Houston, has now established a "prognostic scoring system" to help select such patients.

The system is based on an analysis of 172 patients with metastatic cancer who were enrolled in phase I clinical trials: 105 of them received anti-CTLA-4 drugs, while the rest received anti-PD-1 agents.(Sen, 2018a).

The authors identified seven factors that predicted who would respond best. I have taken the liberty of rearranging these by their hazard ratios (HR), which indicates the increased risk of death associated with each factor:
  1. An absolute lymphocyte count under 1,800 cells per microliter [hazard ratio, HR = 3.3]
  2. An ECOG performance status greater than 1 [HR = 2.81]
  3. An elevated neutrophil count greater than 4,900 [HR = 2.3]
  4. An elevated serum lactate dehydrogenase (LDH enzyme) greater than 466 [HR = 2.1]
  5. The presence of liver metastases [HR = 1.8]
  6. An elevated platelet count over 300,000 [HR = 1.8]
  7. An age of over 52 years [HR = 1.59]
The authors next pooled the patients into four separate groups, based on the number of risk factors that they had. There was a huge difference in overall survival (OS) among these four risk groups:
  1. Group One had 0-2 risk factors: overall survival (OS) = 24.2 months
  2. Group  Two had 3 risk factors = 11.6 months OS
  3. Group Three had 4 risk factors = 8.0 months OS
  4. Group Four was defined as those having 5 or more factors = 3.8 months overall survival (OS)
In those who had zero, one or at most two risk factors, the median survival was thus over two years: and about half of that group was still alive three years after receiving immune therapy. In fact, none of these patients had died after their two-year anniversary of starting treatment. In assessing these figures, remember that all of the patients in this study had advanced disease and had enrolled in these phase I trials as what one might call a "Hail Mary pass" treatment.

Let's now talk about the most important risk factor, the absolute lymphocyte count.

Lymphocytes are a sub-set of white blood cells (leukocytes) that are particularly involved in fighting infections and cancer. In this study, an absolute lymphocyte count under 1,800 cells per microliter (µL) turned out to be the biggest risk factor for failing to respond to ICI therapy. According to the NIH, the normal range of total lymphocytes in an adult is between 1,000 and 4,800 per microliter of blood (µL). But in this study any score under 1,800 µL conveyed a hazard ratio of 3.3 to patients receiving immunotherapy. This is logical, since ICI drugs work by activating the lymphocytes. One would therefore suppose that having fewer lymphocytes would diminish the positive effects of the treatment. But this M.D. Anderson study gives scientific validation of that logical conclusion.

This of course leads to the question of what might cause a decline in the absolute number of lymphocytes. This paper does not discuss the causes of the various risk factors. But one possible cause is cytotoxic chemotherapy, the backbone of the medical treatment of cancer around the world. According to a paper from the Head of the Immunology Section of the National Cancer Institute (NCI):
"Although neutrophil, monocyte, and platelet numbers consistently recovered to greater than 50 percent of pretreatment values after each sequential cycle of [chemo]therapy, lymphocyte numbers did not recover within the same time period...." (Mackall C, 1994, emphasis added)
Lymphocyte depletion following chemotherapy has been well known to oncologists for decades, although many websites addressed to patients underplay the impact of chemotherapy on lymphocytes. For example, an article at the breastcancer.org website claims:
"After finishing chemotherapy treatment, it can take anywhere from about 21 to 28 days for your immune system to recover."
No references are given for this statement. Yet a 2016 study in Breast Cancer Research looked at the long-term impact of chemotherapy on various types of lymphocytes, including B cells, T cells and NK (natural killer) cells:
"Levels of B, T and NK cells [three types of lymphocytes, ed.] were significantly reduced 2 weeks after chemotherapy.... B cells demonstrated particularly dramatic depletion, falling to 5.4 percent of pre-chemotherapy levels. Levels of all cells recovered to some extent, although B and CD4(+) T cells remained significantly depleted even 9 months post-chemotherapy.... ... Breast cancer chemotherapy is associated with long-term changes in immune parameters..." (emphasis added).
Thus, damage may continue for many months, not just a few weeks. While there are a number of possible causes of depleted lymphocytes, in many cancer patients the cause will be cytotoxic chemo as well as radiation therapy. Yet patients are frequently given all possible cytotoxic treatments before doctors will even consider immunotherapy.

It is important to note that this same group at M.D. Anderson also demonstrated that lower doses of immune checkpoint drugs may reduce both toxicity and cost without compromising disease control or survival (Sen, 2018b). [I discuss this in a previous blog.]

In addition, these drugs are enormously expensive. The maximum cost of a single anti-CTLA-4 drug ipilimumab (Yervoy®) is now over USD $1.7 million per patient! (Goldstein, 2017) As a result, this type of therapy is simply not affordable for most people around the world. One can speculate that with better patient selection, and lower doses of ICI, this treatment could become much more affordable for both the individual and society as a whole. This would realistically fulfill the promise of the famous immunologist Carl H. June, MD, that the present moment is only "the tip of the iceberg" of effective immunotherapy of cancer (June, 2017).

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Acknowledgement: My thanks to Tibor Bakacs, MD, PhD, DSc, of the Hungarian Academy of Sciences, Budapest, for his contributions to this blog post.

References:

Goldstein DA. Adjuvant ipilimumab for melanoma—the $1.8 million per patient regimen. JAMA Oncology. 2017;3:1628.

June CH., Warshauer JT, Bluestone JA. Is autoimmunity the Achilles' heel of cancer immunotherapy? Nat Med. 2017;23:540.

Mackall CL, Fleisher TA, Brown MR, et al. Lymphocyte depletion during treatment with intensive chemotherapy for cancer. Blood. 1994;84:2221.

Shiraj Sen, et al. Development of a prognostic score system for patients with advanced cancer enrolled in immune checkpoint inhibitor phase I clinical trials. British Journal of Cancer. 2018; 118:763-769 [2018a].

Sen S, Hess KR, Hong DS, et al. Impact of immune checkpoint inhibitor dose on toxicity, response rate, and survival: A pooled analysis of dose escalation phase 1 trials. Journal of Clinical Oncology. 2018;36:3077 [2018b].







Sunday, October 7, 2018

LOWER-DOSE IMMUNE DRUGS AS EFFECTIVE AS HIGHER DOSES


Kleef clinic, Vienna, Austria

Many of my phone consultees are surprised to hear me say that lower doses of immune checkpoint inhibitor (ICI) drugs are often as effective as the more typical higher doses, with far less toxicity.

Won’t a lower-dose regimen, they wonder, be less effective than the high-dose regimens recommended by the US Food and Drug Administration (FDA) and the drug manufacturers? Well, apparently not. This question was studied in an analysis of clinical trial, which was presented at the 2018 annual meeting of the American Society of Clinical Oncology (ASCO). Here are the conclusions from the University of Texas M.D. Anderson Cancer Center, Houston (home institution of the co-discoverer of immune checkpoint inhibitors):
“Despite a dose-dependent increase in irAE [immune-related adverse events, ed.], we identify no improvement in PFS [progression-free survival, ed.], OS [overall survival, ed.], or DCR [disease control rate, ed.] with escalating doses of ICI [immune checkpoint inhibitors, ed.]...Lower doses may reduce toxicity and cost without compromising disease control or survival."

This is an enormously important finding, which has gotten very little attention in the media. But it is a confirmation of the approach of Ralf Kleef, MD, of Vienna, Austria, who claims excellent results using a lower-than-typical dose of ICI drugs, with far fewer serious side effects, especially when the ICIs are integrated into a holistic immune-stimulating protocol.




Monday, October 1, 2018

ALLISON AND HONJO WIN 2018 NOBEL PRIZE



James P. Allison, PhD, of M.D. Anderson Cancer Center, Houston (l.), and Tasuku Honjo, MD, PhD, of Kyoto University (r.) will share the 2018 Nobel Prize for Physiology or Medicine, the Nobel Committee announced today (October 1, 2018). This was for their work in the discoveries relating to immune checkpoint blockade (ICB) as an effective new cancer treatment. This has firmly established immunotherapy as the fourth modality of cancer treatment (after surgery, radiation and chemotherapy). It has also provide a new way of viewing the battle between cancer and the immune system.

Readers of this blog are familiar with this concept, as I have been writing about it for quite a while now. Almost two years ago I wrote a brief history of immune checkpoint inhibitors, drawing the links between this work and certain pioneers of complementary medicine, such as the great William B. Coley, his daughter Helen Coley Nauts, Lloyd J. Old, Lawrence Burton and others.

Some readers will remember that in my last blog entry, two weeks ago, I concluded with the following words:

"The development of immune checkpoint blockade drugs, first approved in 2011, has been among the most important breakthrough in cancer treatment. I believe that James P. Allison, PhD, of the M.D. Anderson Cancer Center, Houston, is fully deserving of a Nobel Prize in Physiology or Medicine for this epochal discovery." 

So, needless to say, I am excited and gratified by today's announcement from Stockholm.

I also stated, in reference to the recent article by Kleef et al on the use of low-dose immune checkpoint inhibitors in triple negative breast cancer:


"But Ralf Kleef [of Vienna], Tibor Bakacs [of Budapest] and their medical collaborators also deserve great credit, since they have paved the way for a safer and more effective method of using these same agents."

Today's announcement fully justifies the excitement that many in the cancer field feel about the development of immune checkpoint inhibitors. Through the work of Kleef, et al., these drugs can be skillfully incorporated into a holistic and complementary regimen to reduce side effects (which can be serious or severe) and improve the clinical outcome for many patients.



Friday, September 14, 2018

TRIPLE NEGATIVE BREAST CANCER: A HIGHLY SIGNIFICANT FINDING

Ralf Kleef, MD, Vienna, Austria

In mid-September 2018, the medical journal Integrative Cancer Therapies (SAGE), published a peer-reviewed article on a highly significant finding in breast cancer from a European integrative cancer clinic. Here is a link to the full article:

http://journals.sagepub.com/doi/10.1177/1534735418794867

The title is self-explanatory: "Complete Clinical Remission of Stage IV Triple-Negative Breast Cancer Lung Metastasis Administering Low-Dose Immune Checkpoint Blockade in Combination With Hyperthermia and Interleukin-2."


The paper is the result of an international collaboration that involved more than two years of intense effort by scientists in five countries. The first author is the treating physician, Ralf Kleef, MD, of the Kleef Clinic, Vienna, Austria. The other authors are Prof. A. Marcell Szasz of Semmelweis University, Budapest and Lund University, Sweden; Dr. Arthur Bohdjalian of the Rudolfinahaus Hospital, Vienna's leading private hospital; Prof. Hans Bojar of the NextGen Cancer Group, Dusseldorf, Germany; and Tibor Bakacs, MD, PhD, DSc, of the Hungarian Academy of Sciences. I (RWM) am the second author of the article.


In this paper, we report on the case of a 50-year-old woman with breast cancer who experienced disease recurrence at the axillary (armpit) lymph nodes and, later on, lung metastases in both lungs with severe shortness of breath.


The woman in question received low-doses of two Food and Drug Administration (FDA)-approved immune checkpoint blockade drugs (nivolumab {Opdivo®} and ipilimumab {Yervoy®}) weekly over 3 weeks. She also received regional hyperthermia (heat therapy) 3 times a week. This was followed by systemic fever-range hyperthermia induced by another FDA-approved drug, interleukin-2 (IL-2) for 5 days. The patient then went into a complete remission of her lung metastases with only transient grade I-II diarrhea and skin rash. The patient remained alive for 27 months after the start of this treatment. Eventually, there was a recurrence of metastases as a sternal mass, and up to 3 cm pleural metastases and she passed away in the summer of 2017. 

The authors concluded that this exceptional response should instigate further research efforts with this protocol, which consisted only of FDA-approved drugs and treatments. We believe that at these reduced doses, when combined with complementary treatments such as hyperthermia, the results are at least as good as with conventional higher doses, and the rate of serious side effects is concomitantly lower.


A patient with such far advanced lung metastasis would typically have had an extremely 
limited expected survival. Therefore, we wanted to report this case as an exceptional response to lower-dose immune checkpoint blockade therapy, resulting in a more than two year survival from the beginning of immune treatment.

The idea of using a lower-than-typical doses of immune checkpoint drugs was derived from a January 2014 article in the peer-reviewed journal Pharmacological Research. The authors of that pioneering article were Prof. Shimon Slavin, of Tel Aviv, Israel and Dr. Tibor Bakacs of Budapest. (Again, I was second author.) Here is the link:


https://www.ncbi.nlm.nih.gov/pubmed/?term=bakacs+moss+slavin


The development of immune checkpoint blockade drugs, first approved in 2011, has been among the most important breakthrough in cancer treatment. I believe that James P. Allison, PhD, of the M.D. Anderson Cancer Center, Houston, is fully deserving of a Nobel Prize in Physiology or Medicine for this epochal discovery. But Ralf Kleef, Tibor Bakacs and their medical collaborators also deserve great credit, since they have paved the way for a safer and more effective method of using these same agents.




NOTE: Integrative Cancer Therapies has an Impact Factor of 2.657. In 2017, Pharmacological Research had an Impact Factor of 4.897. 
Sources: http://journals.sagepub.com/home/ict and http://www.letpub.com/










Monday, March 12, 2018

EGGS AND PROSTATE CANCER...A WORD TO THE WISE





If you have had prostate cancer (PC), or are at high risk of the disease, it would be prudent to stop eating more than an occasional egg, especially if you live in North America.

Interest in this topic began in 2004, but the thinking at that time was that eggs were innocuous. But this was followed by a “bombshell” study from the Harvard School of Public Health, Boston, showing that “greater consumption of eggs…was associated with [a] 2-fold increases in risk” of a diagnosis of fatal PC compared to men who consumed the fewest number of eggs. A 2011 follow-up study from the same group found that “men who consumed 2.5 or more eggs per week had an 81 percent increased risk of lethal prostate cancer compared with men who consumed less than 0.5 eggs per week.” This led to considerable publicity in the United States.

A follow-up 2015 study found a 47 percent increased risk of life-threatening prostate cancer. A 2016 study from the same group similarly found that high intake of eggs was associated with a doubled risk of advanced PC. 

These are observational studies, of the kind that can find correlations, but do not provide proof that eggs themselves cause PC. That idea is simplistic, in any case. (The Chinese have the highest rate of egg consumption in the world and also one of the lowest rates of fatal PCs.) But there is a biochemical mechanism by which eggs could plausibly promote PC: yolks contain an abundance of choline, a B-vitamin like substance that is found abundantly in prostate cancer. The Harvard authors also found that men with the highest intake of choline had a 70 percent increased risk of being diagnosed with lethal prostate cancer. (Choline is even the basis of an FDA-approved PET scan for prostate cancer.)


The studies in question did not take into account the quality of the eggs consumed. Could it be that American or Canadian commercial eggs are harmful, but that eggs from organic free-ranging chickens are not? Eggs are the basis of a huge mass production business in the United States. To quote the American Egg Board:
“In the major egg producing states, flocks of 100,000 laying hens are not unusual and some flocks number more than 1 million. Each of the roughly 280 million laying birds in the U.S. produces from 250 to 300 eggs a year. In total, the U.S. produces about 75 billion eggs a year, about 10 percent of the world supply.”
These hens are often kept in so-called ‘battery cages” the size of a piece of letter paper! Hens may be starved to increase their egg production. 

Could this production method, or other factors in the production, distribution and consumption of eggs, contribute to the production of unhealthy eggs in the US? We don’t know, but there is a measurable chemical differences in eggs from hens that are raised in cages vs. those that are free-ranged or are enriched with n-3 polyunsaturated fatty acids (PUFA).

There is another important insight contained in the CapSURE study:
“When associations were analyzed separately by geographical region (North America vs. other continents), positive associations between…egg intake…and advanced…and fatal cancers were limited to North American studies….Observed differences in associations by geographical region warrant further investigation” (emphasis added).

Since these effects were limited to North America, it raises the question of whether there is something in the way American eggs are raised or prepared that could account for their particular harmfulness. According to Business Insider:

“In the US, large-scale laying houses are preferred over the free-range systems commonly used in the UK [and many other countries, ed.]. The factory farm environment means more eggs can be produced on a smaller amount of land, but it also makes eggs more susceptible to contamination….”

Could the increased diagnosis of fatal prostate cancers be limited to factory farm-produced eggs in the United States and Canada?  Definitely. But, in the meantime, I recommend erring on the side of caution: I would suggest that all PC patients, or others at high risk, cut back or eliminate their consumption of all eggs, especially the yolks. It is the prudent thing to do.

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Acknowledgement: Thanks to Dr. Geo Espinosa for bringing this topic to my attention through his blog at www.drgeo.com


References:



Keum N, Lee DH, Marchand N, et alL. Egg intake and cancers of the breast, ovary and prostate: a dose-response meta-analysis of prospective observational studies. Br J Nutr. 2015 Oct 14;114(7):1099-107.

Wilson KM, Mucci LA, Drake BF, et al. Meat, Fish, Poultry, and Egg Intake at Diagnosis and Risk of Prostate CancerProgression. Cancer Prev Res (Phila). 2016 Dec;9(12):933-941

Richman EL, Kenfield SA, Stampfer MJ, et al. Egg, red meat, and poultry intake and risk of lethal prostate cancer in the prostate-specific antigen-era: incidence and survival. Cancer Prev Res (Phila). 2011 Dec;4(12):2110-21

Sunday, February 18, 2018

REVISED BLOG--HYPERTHERMIA EXTENDS SURVIVAL




Photo: Prof. Rolf Issels, MD, Munich, Germany

NOTE: This is a revised version of my blog/newsletter from earlier today. I have made several changes. First, the publishing journal is JAMA Oncology (not Lancet Oncology). Second, I have clarified the nature of the survival advantage by quoting the article's authors. Third, I have removed the previous photo, since it did not represent the type of hyperthermia used in this experiment.

------

On February 15, JAMA Oncology published a phase III randomized controlled trial (RCT) on the use of regional hyperthermia (heat therapy) with chemotherapy for soft tissue sarcomas. As this landmark paper points out, "Patients with soft tissue sarcoma are at risk for local recurrence and distant metastases despite optimal local treatment." Preoperative chemotherapy improves the outcome somewhat. But the authors' theory was that adding targeted heat therapy might improve the outcome even more.

A clinical trial to test this hypothesis began in 1998 and it has taken two full decades to finally prove that heat therapy improves both progression-free (PFS) and survival (OS). Thus, out of 341 patients treated, a total of 220 experienced disease relapse, and 188 died. But the addition of regional hyperthermia improved progression-free survival (PFS) by 35 percent. The true bottom line for patients and their loved ones is whether they live longer. The really exciting news is that survival was also prolonged vs. preoperative chemo alone. Here is how the authors phrase it:

"Patients randomized to chemotherapy plus hyperthermia had prolonged survival rates compared with those randomized to neoadjuvant chemotherapy alone...with 5-year survival of 62.7%...vs 51.3%..., respectively, and 10-year survival of 52.6%...vs 42.7%."

That could results in a great many lives saved through a relatively safe and simple procedure.

Writing in JAMA Oncology, the 21 authors concluded:
"Among patients with localized high-risk soft tissue sarcoma the addition of regional hyperthermia to neoadjuvant chemotherapy resulted in increased survival, as well as local progression-free survival. For patients who are candidates for neoadjuvant treatment, adding regional hyperthermia may be warranted."
The study was headed by Prof. Rolf Issels, MD, of University Hospital Medical Center, Großhadern, Munich. Although a mainly European multi-national effort, there were American participants at the University of Maryland Medical Center.  Nonetheless, the study has a global significance that goes far beyond its applicability to relatively rare sarcomas. 

Hyperthermia has been scorned as "alternative medicine" for decades. Mainly through the work of scientists in Rotterdam, Holland, it was eventually acknowledged as a way to help delay progression of the disease. But there remained skepticism that it actually extended human survival. Now through this meticulous multi-national study, it has now been conclusively proven to do so in a type of cancer that is notoriously difficult to treat.

JAMA Oncology is ranked #8 among the top 217 oncology journals in the world. But will this study really change anything? Skepticism towards hyperthermia still runs very deep. This is compounded by the fact that this treatment is not a mass-produced drug, but relies on a natural treatment, heat. It  requires the purchase and maintenance of expensive equipment and, more importantly, the training of highly skilled technical personnel to administer the treatment. Few hospitals have proven willing to make such an investment. Perhaps this study will change all that.

When these results were first announced at a medical conference in Hawaii in November,  it garnered a mere two articles in obscure medical publications. And, so far, this JAMA Oncology publication has not been picked up by any news service or online journal. Perhaps discussions at the forthcoming Society of Thermal Medicine (STM) meeting in Tucson, Arizona (May 7-10) will generate more well-deserved attention for this important finding.

To be clear, hyperthermia is not a stand-alone "cure," but an adjuvant treatment that must be added to other approaches. It lacks the sexiness of purported "magic bullets," of the type that appeal to Wall Street investors. But it fits in very well with the holistic approach that is favored by many private clinics in the non-English speaking world, especially in the German-language zone. This study should be a powerful stimulus to the further employment of such treatments.

To read an abstract of the JAMA Oncology paper in question:







Thursday, February 15, 2018

SIDE EFFECTS OF IMMUNE CHECKPOINT DRUGS



For the past three years, the American Society of Clinical Oncology (ASCO) has declared cancer immunotherapy to be the "breakthrough of the year." An important part of this approach comes from a class of drugs known as immune checkpoint inhibitors.

I share the general enthusiasm for this approach, but I also have caveats. One of these is the likelihood of patients experiencing serious side effects (technically known as "immune related adverse events" or irAEs) at typically recommended doses.

According to Igor Puzanov, MD, of Roswell Park Cancer Institute, Buffalo, NY:
"New immunotherapy agents are being approved at a rapid pace, and patients have new treatment options, but 'many of these agents have side effects we haven't seen before. We're seeing effects on the skin, lungs, gastrointestinal and endocrine systems, joints, heart and other organs, and some of these are only just beginning to be described'" (all emphases are added).
We must collectively resist the "gold rush" atmosphere that some drug companies have generated around their new cancer treatments. Immune checkpoint inhibitors are not magic bullets for cancer or anything else. They are, however, very useful tools that can be used as part of a safer holistic  approach to cancer. For various reasons, this type of approach is only available at clinics that are not beholden to the international medical-industrial establishment.

While side effects with immune checkpoint drugs are different than with most chemotherapies, they can also be extremely serious and difficult to treat. According to the same Medpage Today article:


"Serious and occasionally life-threatening immune-related adverse events have been reported in the literature, and treatment-related deaths occur in up to 2 percent of patients, varying by checkpoint inhibitor."
According to a review article on the immune checkpoint drug ipilimumab (Yervoy®):
"Single cases of unpredictable, in part astonishing, and difficult to treat, life-threatening or even fatal side-effects, have been reported including cases of nephropathy, myopathy, sarcoidosis, Guillain-Barré syndrome, uveitis, and leucopenia."
This should not come as a surprise. In June 2012, my colleagues Tibor Bakacs, MD, PhD, DSc, of the Hungarian Academy of Sciences, Jay Mehrishi, PhD, then of the University of Cambridge, UK, and I published one of the first medical journal articles warning of the potentially "catastrophic" effects of these drugs. We warned that,
"147 (38.7%) of the patients experienced severe adverse events and 6.8% suffered dose-limiting events (8.4%, in the ipilimumab-alone group). There were 14 deaths related to the study drugs and 7 of these were associated with immune-related adverse events. In contrast, the complete response rate was only 0.2%, in one patient out of 403 who received ipilimumab plus a peptide vaccine."
This is the reason that some European oncologists prefer a low-dose combined approach to immune checkpoint inhibition. By this, they mean that two such agents can be used simultaneously, in conjunction with other immune-stimulating and natural treatments. The side effects with such a low-dose approach are generally mild and infrequent. It is a sane, and humane, way to use these powerful new agents.

References:


ASCO Advance of the year 2018: https://www.asco.org/research-progress/reports-studies/clinical-cancer-advances-2018/advance-year


Source of the Dr. Puzanov quote: https://www.medpagetoday.com/reading-room/asco/immunotherapy/71026?xid=NL_ASCORR_2018-02-15&eun=g5387475d39r&pos=1 

My coauthored article on ipilimumab: Bakacs T, Mehrishi JN, Moss RW. Ipilimumab (Yervoy) and the TGN1412 catastrophe. Immunobiology. 2012 Jun;217(6)583-9.



Friday, January 19, 2018

LETTER IN SCIENCE TRANSLATIONAL MEDICINE



My colleague, Tibor Bakacs, MD, PhD, DSc, of the Hungarian Academy of Sciences, and I have just had an e-letter published in the journal Science Translational Medicine (STM). STM is an offshoot of Science, the weekly magazine of the American Association for the Advancement of Science (AAAS). STM has an impact factor of 16.789, making it the 11th most influential journal in the entire medical field. (The impact factor reflects the yearly average number of citations to recent articles published in a journal.)

STM is a kind of "Formula 1" testing ground for medical science. In other words, cutting-edge medical technology usually debuts here in an atmosphere of fierce competition for space and attention. As an example, the paper we were commenting on was written by 39 authors from top institutions. It pertains to one of the most promising breakthroughs in cancer therapy--the combination of immunotherapy with cancer-killing (oncolytic) viruses. This is the subject of intense research at Sloan-Kettering Institute, M.D. Anderson Cancer Center, and many other centers.

Our 900 word e-letter demonstrates several important point that could positively impact the worldwide discussion. We show that an un-engineered Newcastle Disease Virus (NDV) vaccine is still superior to anything coming from Big Pharma. We illustrate the "proof of principle" case of a wheelchair-bound Israeli patient, with a grade IV recurrent glioblastoma multiforme (GBM) and a Karnofsky performance score of 40, who experienced a complete and long-lasting remission through the use of an attenuated Newcastle vaccine called MTH-68. This patient is alive and well more than 20 years after his complete remission. According to the consensus of experts GBM is incurable. The median survival for grade IV GBM after tumor- directed surgery and chemoradiotherapy is 14.6 months. We found no other high grade, recurrent GBM case published in PubMed, which comprises more than 27 million citations for biomedical literature from MEDLINE, life science journals, and online books.

The fact that this remission came about through the repeated use of an attenuated non-engineered virus is a very important observation. It means that the virus can be administered safely and in a virtually non-toxic fashion almost anywhere in the world.

Dr. Bakacs and I met in the early 1990s through our mutual friendship with the brilliant late Hungarian-American general practitioner, Laszlo Csatary, MD of Alexandria, VA. Bakacs is a clinically trained scientist with over 30 years experience, author of 75 scientific papers in leading medical journals. We have remained close friends and collaborators for decades.

In 1999, Csatary and Bakacs, et al. published a letter on this exceptional case in the Journal of the American Medical Association. In the same year, I joined them, along with Josef Beuth, MD, of the University of Cologne, in a more comprehensive case series on the beneficial effects of NDV.

In 2013, the Israeli patient's physician, Arnold I. Freeman, MD, of Hadassah Hospital, Bakacs and I published a follow-up review of this exceptional GBM case in the Journal of Clinical Oncology.

In the past, Dr. Bakacs and I often found our articles and letters on this topic rejected by the major journals. (This is a saga in itself.) Nonetheless, we continued to publish in less impactful scientific journals. We are now guardedly optimistic that our perspective on NDV will be heard by those who are in a better position to change the course of treatment.

We are well aware of the formidable barriers to acceptance that remain for non-toxic, inexpensive and widely available treatments. In addition to confronting scientific dogma, one also has to confront the economic barriers to acceptance.

This takes some explaining.

It takes many millions of dollars to gain approval for new treatments. Some people have pegged the cost of developing a new drug at $2.6 billion! Although this is probably exaggerated, the process is still exceedingly expensive. This high cost actually serves the interests of Big Pharma, since it serves as a barrier to the entry of inexpensive drugs into the marketplace. 

The high cost of drug development then becomes the main justification for charging unconscionable amounts for new drugs. For example, in 2017 the Food and Drug Administration (FDA) approved a new form of cancer immunotherapy (called Kymria®) at $475,000 for a single infusion!

This has created a "gold rush" atmosphere around cancer drugs. No profit-driven company is likely to develop a simple natural treatment in such an atmosphere. Treatments made from attenuated non-engineered viruses are too readily available to be of much interest to Big Pharma. Most of the talk these days is of engineered forms of the virus. This means producing unique and patentable forms, which cannot be easily "knocked off," and whose sale can be legally monopolized for years. That's where the big money is. But if inexpensive vaccines are eliminated in favor of highly expensive engineered ones, this will also have disastrous consequences for billions of people worldwide. They will not be able to afford the treatment, or will be bankrupted in the process. So a great deal is at stake in how this debate over NDV is resolved.


References

2018 Science Translation Medicine e-letter:


http://stm.sciencemag.org/content/10/422/eaam7577/tab-e-letters

Research into bioengineered forms of Newcastle Disease Virus Vaccine:

Zamarin D, Holmgaard RB, Ricca J, et al. Intratumoral modulation of the inducible co-stimulator ICOS by recombinant oncolytic virus promotes systemic anti-tumour immunity. Nat Commun. 2017 Feb 13;8:14340. 


1999 Review of NDV in Anticancer Research:

Csatary LK, Moss RW, Beuth J, Töröcsik B, Szeberenyi J, Bakacs T. Beneficial treatment of patients with advanced cancer using a Newcastle disease virus vaccine (MTH-68/H). Anticancer Res. 1999 Jan-Feb;19(1B):635-8.

Freeman, Bakacs, Moss Abstract in the JCO:

http://ascopubs.org/doi/abs/10.1200/jco.2013.31.15_suppl.e13029

Cost of Kymria: 

http://www.onclive.com/web-exclusives/novartis-sets-a-price-of-475000-for-car-tcell-therapy


Cost of new drug development:

https://www.nytimes.com/2014/11/19/upshot/calculating-the-real-costs-of-developing-a-new-drug.html