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Hyperthermia moves to fore as CAM treatment of cancer.

Hyperthermia refers to heating a particular region of the body or heating the whole body, in order to fight cancer. Hyperthermia works by (a) directly killing cancer cells, which are uniquely susceptible to heat; (b) activating natural killer (NK) cells, macrophages, and other components of the immune system; and (c) creating heat shock proteins (HSPs), which can damage cancer cells. At my website, I have discussed in some depth the origins of hyperthermia in the work of William B. Coley, MD, a pioneer of immunotherapy in the late 19th and early 20th centuries. Coley's toxins remain difficult to access, especially in the US. But hyperthermia continues to pick up steam, as I shall explain below.

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Hyperthermia Advances in Germany and America

Travel is broadening, and nowhere more so than in the comparison of innovative medical treatments. I am in fact writing these words in southern Germany, where I am visiting various cancer clinics that use unconventional methods in the treatment of cancer. As I complete this tour of German clinics, I am struck by the degree to which certain treatments are viewed as routine by many people in this part of the world but are considered daringly "alternative" in the US. The gap is particularly glaring in the case of hyperthermia.

Germany and the US each played a pioneering role in the use of hyperthermia in treating cancer. The equivalent of Coley in Germany was Wilhelm Busch, a professor of surgery at the University of Bonn, who first used bacterial vaccines in Germany. In hyperthermia, Germany had the famous Dr. Manfred von Ardenne and his East German institute, where he worked out much of the physics of delivering heat to tumors.

But the US, too, was a leader. I remember one memorable article on the topic in the journal of the American Medical Association (JAMA), where the authors, headed by Harry H. LeVeen, MD, reported that ultrasound waves could be used to heat and destroy tumors. They were able to "eradicate" (their word) animal cancers without destroying the adjoining normal tissue. The authors reported: "Radiofrequency therapy produced tissue necrosis or substantial regression of cancer in 21 patients" (LeVeen 1976). When ultrasound waves were directed at a malignant lung, the tumor was then superheated to 106 to 107 [degree]F, but the healthy tissue was cooled by normal blood circulation and protected from harm (New York Times, Jan. 7, 1997).

As a young science writer at Memorial Sloan-Kettering Cancer Center, I nervously phoned the lead author of that piece, LeVeen, chief of surgery at the Veterans Affairs Medical Center in Brooklyn. This wasn't exactly part of my job, but I was just so fascinated by the work that I had to call. LeVeen assured me that hyperthermia would soon be accepted as "fourth modality" in cancer therapy (after surgery, radiation, and chemotherapy). Alas, that was over 30 years ago! Half the present population of the US wasn't even born when I made that call. And needless to say, hyperthermia is still not available for the vast majority of American patients.

In the US, hyperthermia struggles for recognition and acceptance. Many oncologists seem only dimly aware of developments in this field, or in other treatments that are popular in continental Europe, Asia, or other parts of the world. In Germany and its neighbors, by contrast, hyperthermia is increasingly accepted as a useful adjuvant treatment for selected cancers.

If you put the search terms "thermotherapy" (a more precise term for hyperthermia) and "cancer" into the PubMed article database, you come up with about 8,500 articles. Of these, 158 refer to randomized clinical trials. You can sample these articles to see the potential power of adjuvant hyperthermia. For example, in Guangzhou, China (a city I also enjoyed visiting last year), interventional radiologists recently added hyperthermia to other therapies in the treatment of primary liver cancer. The three-year survival rate with standard treatment was 23%. But when hyperthermia was added, the survival rate soared to 51% (Lu 2008). This is not a fluke. It is representative of many articles on the clinical effects of hyperthermia, which can double the effectiveness of more conventional treatments.

The BSD Medical Corporation, based in Salt Lake City, makes heroic efforts to gain acceptance for hyperthermia in the US. For example, in May it attained a Humanitarian Use Device (HUD) designation for the Company's BSD-2000 Hyperthermia System for use in conjunction with radiation therapy for the treatment of some cervical carcinoma patients. Following receipt of this designation, the company has filed for a Humanitarian Device Exemption (HDE) from the Food and Drug Administration (FDA), which is currently under review. But, as a cancer patient, try to get hyperthermia treatment in an American hospital and you will mostly experience frustration.

Invented Here, Sold There

There is a pattern to America's failure to adopt its own innovations. There is no question that American scientists and inventors innovate well, but then the country frequently drops the ball when it comes to implementation. Apropos of this, on September 15, 2009, New York Times columnist Thomas L. Friedman wrote a perceptive article on how one American company had invented new machinery to manufacture solar energy panels. The company has 14 factories around the world; five in Germany, and four in China. But none are in the US, where the company itself is based. "Invented here, sold there," is America's slogan, says Friedman. Germany, in particular, now generates almost half the solar power in the world and is making itself the "world-center for solar research, engineering, manufacturing and installation." This has added 50,000 new jobs, making renewable energy its second largest industry after auto. (I saw solar panels on roofs everywhere I traveled in Germany.)

I would suggest that the same thing is happening with hyperthermia. Americans have figured out how to pair the BSD's hyperthermia equipment to GE Healthcare 1.5 Tesla magnetic resonance (MR) imaging system for precise hyperthermic targeting of tumors. (Siemens produces similar equipment in Germany.) A prototype of the BSD-GE hybrid was recently installed at Duke University School of Medicine in North Carolina. It can be electronically focused to target the three-dimensional shape, size, and location of the tumor and provide a dynamic form of control over the heat delivery. Good for Duke! Such systems will no doubt become the wave of the future. But let me make a prediction. Do not expect to see find devices like this at a typical American cancer center any time soon. If you want to have a reasonable chance of adding hyperthermia (and other innovative treatments) to your own protocol, you will still have to go to Germany, China, or some other innovative country. "Invented here, sold there" is the rule in integrative oncology as well.

Intergroup Trial of High-Risk Sarcoma

On September 23, there was more good news about the effects of heat on cancer. Rolf Issels, MD, PhD, professor of medical oncology at the Klinikum Grosshadern Medical Center at the University of Munich, presented the results of regional hyperthermia (RHT) at a press conference in Berlin. This was presented as part of Europe's largest cancer congress. The final results were surprisingly robust.

Issels reported on 341 patients with high-risk sarcomas who received a standard chemotherapy regimen consisting of three drugs: etoposide, ifosfamide, and adriamycin. Half of the patients were then randomized to receive hyperthermia before and after their chemotherapy. The median follow-up time was 34 months.

Adding RHT to chemotherapy had many reduced the risk for recurrence or death by an astonishing 42%. Patients who were assigned to the combination treatment survived an estimated 120 months before progressing, compared with 75 months for those who were assigned to chemotherapy alone.

The improvement in overall survival (OS) was not significant in the intent-to-treat population. That may have been because some patients dropped out because of the toxicity of the chemotherapy and thus never received the full course of combined treatment. However, patients who did complete all four cycles of chemotherapy as well as eight hyperthermia treatments were 44% less likely to die during follow-up compared with those who were assigned to chemotherapy alone. Forty-four percent!

There were other signs of the benefit of adding heat to conventional treatment. After two years, 76% of patients assigned to the combination therapy were alive without local progression, compared with 61% of those assigned to chemotherapy alone. Tumor shrinkage occurred in just 12.7% of patients assigned to chemotherapy alone vs. 28.8% assigned to combination therapy. In addition, tumor growth occurred in 6.8% of those assigned to combination therapy vs. 20% of those assigned to chemotherapy alone. Here is a chart that makes the comparison quite clear (Table 1):
Table 1: Two-Year Responses to EIA Chemo with or without Regional
Hyperthermia (RHT) in Patients with High-Risk Soft-Tissue Sarcomas

            Alive w/o local progression  Tumor shrinkage  Tumor growth

Chemo                   61%                   12.7%           20.0%
Chemo +RHT              76%                   28.8%            6.8%


Prof. Issels described this as "the first--and the only completed--randomized study on neo-adjuvant chemotherapy in high-risk soft tissue sarcoma showing that the addition of regional hyperthermia significantly improves ORR [overall response rate], TTP [time to progression], LPFS [local progression-free survival], and DFS [disease-free survival]."

Researching the kind of treatment described in this paper has been Rolf Issels's life work for over 20 years. There were about 150 leading groups studying the combination therapy, mostly in Europe. According to Prof. Issels, "The clear results of this trial show that the field has now matured to the point where we must step up efforts to explore its potential to offer an entirely new way of treating locally advanced disease in several major cancers."

A Brief History of Hyperthermia

One can find references to the use of heat, or fever, to treat cancer in ancient literature, including that of ancient Egypt and Greece (Breasted 1930). As indicated, intense interest in heat therapy was stimulated by the observations of Coley (and his predecessor, Prof. Busch) that infections and fevers could sometimes lead to the regression of tumors.

Dr. Leo Loeb, a German-American pathologist, showed that cancer could not be transplanted into experimental mice if the temperature of the section in question was previously heated 13 [degrees]F above the human normal (i.e., 111.6 [degrees]F). (1) He and his coworker, Dr. Moyer S. Fleischer, produced "various degrees of virulence" in cancer cells "through a graded effect of moderate heat" (AACR 1912).

One of the unsung heroes of hyperthermia was James Fulton Percy, MD. Around the time of World War I, Percy published an article in JAMA on the use of heat in cancer (1914). Percy understood that it was not necessary to burn cancer, but simply to raise its temperature to the point where malignant tissue was preferentially destroyed. Oddly, he thought that normal tissue died at 132 [degrees]F to 140 [degrees]F (55 [degrees]C to 60 [degrees]C), whereas cancer died at 113 [degrees]F (45 [degrees]C). Today oncologists use far lower temperatures. But Percy was on the right track when he pointed out that "many surgeons who are making use of the method still have the idea that it is necessary to produce a degree of heat sufficient to burn up the parts involved." High temperatures (such as are involved in modern-day radiofrequency ablation, or RFA) are cautery, not hyperthermia in sense we have described.

James Percy was born in Bloomfield, New Jersey, on March 26, 1864, of Scotch-Irish ancestry. He was educated at New York University and, like many serious scholars of the time, earned a postgraduate degree in Germany in 1896, where he studied with eminent surgeons. In 1923, seeking a wider scope for his practice, he came to Los Angeles County Hospital. Percy, one journalist has written, attacked his patients' cancers with a "glowing, cherry-red soldering iron, considered by some an instrument of quackery and by others a medical marvel" (Rasmussen 1999). This seems like an exaggeration, but his eccentricity was legendary--for instance, he wore a bathrobe to surgical procedures and was sometimes himself mistaken for a psychiatric patient.

Schlenz Bath

Meanwhile, the German-speaking world had its own pioneers. A gentler form of hyperthermia was the warm water bath advocated by a lay healer, Marie Schlenz of Innsbruck, Austria, in the 1930s to 1950s. This was later used by the immunotherapist Josef Issels, MD (who happened to be the father of the above-mentioned Prof. Issels), at his Ringberg Klinik in Tegernsee, Bavaria, as well as Dr. Werner Zabel at his clinic in Berchtesgaden, also in Bavaria. (Zabel wrote a book with Schlenz in 1944.)

In a Schlenz bath, the patient is submerged with only the nose, eyes, and mouth out of the water. The starting temperature is that of normal skin (about 95 [degrees]F), which is then raised slowly to 100 [degrees]F in about 20 minutes, and further to 103 or 104 [degrees]F, if the patient remains comfortable. The whole treatment takes about one hour. It is said that the patient's internal temperature gradually rises to match the water temperature. When given to a sick person, the treatment needs to be carefully supervised. The pulse, Schlenz said, should always remain below 130 or 140. The temperature of the water needs to be measured with a bath thermometer. If the patient feels discomfort, he should be raised out of the water for a while. The Schlenz bath was popular and much discussed, and probably contributed to the ongoing German fascination with heat therapy.

Notes

(1.) Loeb L. Virchows Arch. f. path. A.nat. 1903:clxxii,345; Am. Med. 1905:x,265.

References

AACR. Fifth Annual Meeting, minutes. Boston Med Surg J. 1912;166:740. Breasted JH. The Edwin Smith Surgical Papyrus. Vol.1. Chicago: University of Chicago; 1930.

Bellamy I, MacLean D. Radiant Healing. Queensland, Australia: Joshua Books; 2005. Friedman TL. Have a nice day. New York Times. September 19, 2009.

LeVeen HH, Wapnick S, Piccone V, Falk G, Ahmed Nafis. Tumor eradication by radiofrequency therapy. Responses in 21 patients. JAMA. 1976;235:2198-2200.

Loeb L. Virchows Arch. f. path. A.nat. 1903;62:345; Am. Med. 1905;10:265.

Percy JF. Best methods of discouraging the activity of inoperable cancer. A study of heat in cancer. JAm Med Assoc. 1914;42:1631-1634.

Rasmussen, Cecilia. 2 doctors' actions rocked 'the Rock.' Los Angeles Times, June 27, 1999.

BSD Medical's Web site is www.bsdmedical.com.

An abstract of Issels's 2009 presentation can be found at: http://tinyurl. com/y86b52v.

An earlier analysis of the Issels study was presented at the American Society of Clinical Oncology's 2007 annual meeting: http://tinyurl.com/y8mb36d.

by Ralph Moss, PhD

www.cancerdecisions.com

Ralph W. Moss, PhD, is the author of 12 books on cancer-related topics. The former science writer at Memorial Sloan-Kettering Cancer Center, for 35 years Moss has investigated the validity of many cancer treatments. He currently directs the Moss Reports, a library of reports for patients on over 200 different cancer diagnoses.
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Title Annotation:War on Cancer
Author:Moss, Ralph
Publication:Townsend Letter
Article Type:Report
Geographic Code:4EUGE
Date:Jan 1, 2010
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