War on Cancer – 10-2012

by Ralph W. Moss, PhD

Are We Making Progress in the ‘War on Cancer’?

Part 2

Last issue, I began a discussion of the lack of progress in the 40-year “war on cancer,” especially as it relates to the most common forms of cancer. I conclude my discussion in this issue. This is a version of the speech that I gave in Munich on June 16, 2012, at the 2nd Annual International Conference on Integrative Oncology of the German Society of Oncology (DGO), modified with some more recent data.

Lest you think that the introduction of the so-called targeted agents has greatly improved the situation in lung cancer, here are the results of a paper from the 2012 annual meeting of the American Society of Clinical Oncology (ASCO). In an Italian phase III clinical trial called TAILOR, which compared second-line treatment with the standard drug docetaxel (Taxotere) with the targeted drug erlotinib (Tarceva) in the common or “wild” type of lung cancer (NSCLC), there was:

• a total response rate of 14% with docetaxel vs. 2.2% with erlotinib

• a 3.4-month median progression-free survival with docetaxel vs. 2.4 months with erlotinib

• a complete response (CR) rate of 4.3% with docetaxel vs. 0.0% with erlotinib (Garassino 2012)

As a result, in the discussion period one Bronx, New York, oncologist, Stephen E. Vogl, MD, asked whether a fair summation of this study might be that “docetaxel is not a very good drug and erlotinib is a terrible drug.” When the first author agreed, this was greeted with a “round of laughter and applause” by the ASCO audience (Wendling 2012).

Unfortunately, a similar presentation could be made of the other common cancers, including stage IV esophagus, liver, pancreas, bile duct, sarcoma, and so on. There are only a few bright spots in an otherwise bleak picture. And this is more than 40 years since initiation of President Nixon’s “five-year war” against the disease.

Cost of Treatment

Meanwhile, the cost of research and treatment for cancer has risen to astronomical levels. According to Newsweek, the US spent $100 billion on cancer research from 1971 to 2008. The FY 2011 budget request for the National Cancer Institute was $5.2 billion. According to the Journal of the National Cancer Institute, medical expenditure on cancer reached $125 billion per annum in 2010. This is expected to rise to $158 to $207 billion per annum by 2020.

One driving force in the market is obviously the pharmaceutical industry, particularly the top 20 or so companies represented by the drug lobby, or Big Pharma. This is a long and complicated discussion, since big drug companies obviously do much good in society by providing reliable and effective drugs for many conditions. But there are negative aspects of the growth of an oligopoly in medicines as well.

Cancer is said to be “one of the most important growth segments among the pharmaceutical markets,” according to Business Insights (2009). At $47.7 billion per year for drugs alone, “cancer is one of the largest, fastest growing markets in the pharmaceutical industry” (ibid.).

One disturbing trend is the increasing cost of new anticancer drugs provided by Big Pharma. Here are a few examples of so-called “premium pricing”:

• Avastin (bevacuzumab) for colon, etc. = $88,000 per patient

• Provenge for prostate cancer: $31,000 per injection = $93,000 per patient

• Yervoy (ipilimumab) for melanoma = $30,000 per infusion = $120,000 for four months

• Herceptin + Perjeta = $187,000 p.p. for 18 months (Pollack 2012).

Meanwhile, many inexpensive drugs are in short supply, possibly because of a lack of profitability compared with the newer targeted agents. To quote a physician, writing in Forbes: “Generic drugs which are off patent that are costly to produce, but usually cheap to purchase, are generally the medications in short supply” (Glatter 2012).

If anyone still thinks that the solution to the cancer problem will come from the “targeted” agents (the “-mibs, -mabs, -nibs and -nabs” as one wit called them), August brought sobering news. Amgen, the world’s largest biotechnology company, announced that it was stopping a late-stage clinical trial of ganitumab (AMG 479) for pancreatic cancer. The drug targets the type 1 insulin-like growth factor receptor, which helps regulate cell growth. An independent monitoring committee concluded that the drug wasn’t adding anything to standard chemotherapy. According to Bloomberg.com, three other drugs of similar design (Pfizer Inc.’s figitumumab, Sanofi’s AVE 1642, and Roche Holding AG’s RG1507 have also failed in recent days; Bloomberg 2012).

Sean Harper, executive vice president of research and development at Amgen, blamed the intractability of the disease. “These disappointing results underscore the difficulty of treating pancreatic cancer,” he said in a statement. They also underscore the futility of using single “targeted” drugs to try and stop a disease that probably relies on many “driver mutations” to fuel its growth.

Role of CAM

There is no simple solution to this complex problem. However, I would suggest that one underutilized resource is complementary and alternative medicine (CAM). This is a repository of new concepts and treatments. Some are undoubtedly ineffective. But, in our lifetime, we have seen two important treatments that for a decade were branded as quackery (i.e., immunotherapy and hyperthermia) transition into conventionally accepted treatment modalities. So a special program should be launched to dip into the treasury of CAM for fundamentally new treatment ideas.

I would also argue that the results with integrative oncology (IO); that is, a combination of conventional oncology and CAM, might turn out to be better than when using conventional oncology alone. This at least is suggested by the careful study of Keith Block and colleagues, showing that stage IV breast cancer patients at a private CAM clinic in a Chicago suburb had 38 months’ overall survival compared with 20 months at similar non-CAM center. To quote the paper: “There currently is no drug that has demonstrated the potential to double the life expectancy of metastatic breast cancer patients, as evidenced in these findings” (2009).

My conclusions are therefore as follows:

1. Progress in the War on Cancer, when measured by improvement of survival in stage IV disease, has generally been disappointing.

2. The needs of Big Pharma basically drive major developments in oncology.

3. Cancer is and remains Big Business.

Fundamentally new strategies are necessary to bring about major changes. CAM is a repository of such ideas. A considerable amount of attention should be paid to the serious exploration of such ideas, up to and including the performance of definitive randomized controlled trials of the best CAM concepts.

Progress in Hyperthermia

Talking of pancreatic cancer, one of the great hopes of the CAM movement is hyperthermia, which is the use of therapeutic heating to treat cancer. A recent study adds “fuel to the fire” as it were in favor of this treatment. In a study from the Kyoto Prefectural University of Medicine, T. Ishikawa and colleagues reported on the results of a phase II trial of hyperthermia plus chemotherapy for unresectable advanced pancreatic cancer (2012).

The standard drug gemcitabine (Gemzar) was administered intravenously on days 1, 8, and 15 every 4 weeks. Regional hyperthermia was then performed once weekly. The primary end point was the 1-year survival rate. The authors enrolled 18 patients between November 2008 and May 2010. The objective response rate (ORR) and disease control rate (ORR + stable disease) were 11.1% and 61.1%, respectively. Median overall survival (OS) was 8 months, and the 1-year survival rate was 33.3%. Median OS of patients with locally advanced pancreatic cancer was 17.7 months. The authors concluded that “regional hyperthermia combined with gemcitabine is well tolerated and active in patients with locally advanced pancreatic cancer.” Because this was not a randomized trial, it is impossible to say how well the patients would have done without the added heat. However, a disease control rate of 61.1% strikes me as very good in this patient population.

This year saw a little forward motion in the glacial progress of hyperthermia in the US. The Food and Drug Administration (FDA) gave approval to the BSD-2000 Hyperthermia System. This was the machine that was used in the two randomized trials of local-regional hyperthermia in Europe: the Munich-based trial in soft tissue sarcoma (STS) and the Rotterdam-based trial in stage II–III cervical cancer. In both those cases, there was significant benefit to the affected patients (see below).

According to a statement on the FDA’s website, the machine in question is intended to deliver focused therapeutic heating with temperatures greater than 104 ºF (40 ºC), to cancerous tumors by applying radiofrequency (RF) energy at the frequency range of 75 to 120 MHz. (The term RF energy is a general term that refers to frequencies above audio and below light. The terms radiofrequency [RF], electromagnetic [EM], or microwave [MW] are used interchangeably to refer to this frequency range.)

The BSD-2000 delivers RF energy to a patient using a power source and an array of antennae that surround the patient’s body. The energy delivered by the BSD-2000 can be electronically focused to produce a localized EM power field. This can be adjusted to target the 3-dimensional shape, size, and location of the tumor, providing dynamic control of the heat delivered to the tumor region. This method of therapeutic heating utilizes the adjustment of frequency, phase, and amplitude from multiple power sources, along with an applicator selection and patient positioning, to optimize heating of the targeted body tissues (FDA.gov)

The FDA approval was granted for a very narrow indication; that is, “in conjunction with radiation therapy for the treatment of cervical cancer patients who are ineligible for chemotherapy.” The fundamental purpose, said the FDA, is that such treatment “increases the response of tumor cells to radiation therapy.” But hyperthermia is useful in many forms of cancer, and so it remains to be seen whether the few cancer centers that are buying and installing this device will extend “off-label” use to a broader range of patients. Meanwhile, it’s official. Hyperthermia works!

EORTC-ESHO Intergroup Trial of High-Risk Sarcoma

As I reported in these pages several years ago, although the hyperthermia equipment in question was “made in USA,” the current push towards hyperthermia comes on the heels of two highly significant clinical trials in Europe.

Rolf Issels, MD, PhD, professor of medical oncology at the Klinikum Grosshadern Medical Center, University of Munich, presented the results of the regional hyperthermia (RHT) trial in soft-tissue sarcoma (STS) at a press conference in Berlin on September 23, 2009. This conference was held in conjunction with Europe’s largest cancer congress.

The final results using hyperthermia in high-risk sarcoma were surprisingly robust. Thus, Issels (son of the famous alternative cancer doctor, Josef Issels, MD) reported on 341 sarcoma patients who received a chemotherapy regimen. This consisted of three standard drugs: etoposide, ifosfamide, and doxorubicin. 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 reduced the risk for recurrence or death by a very impressive 42%. Patients who were assigned to receive additional heat treatment survived an estimated 120 months before progressing compared with 75 months for those who were assigned to chemotherapy alone.

There were other signs of benefit by 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 28.8% assigned to combination therapy vs. 12.7% of patients assigned to chemotherapy. In addition, tumor growth occurred in 6.8% of those assigned to combination therapy vs. 20% of those assigned to chemotherapy alone.

Rolf Issels described this at the time 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 the overall response rate, time to progression, local progression free survival, and disease free survival.”

According to 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.” (Moss, 2010).

These results with hyperthermia are intrinsically important for the various cancers mentioned. But the accumulating data on the benefits of hyperthermia (as an addition to standard therapy) gives the lie to the idea that American oncologists will adopt any therapeutic measure, provided that it is proven effective in randomized clinical trials (RCTs). In my opinion, a great many American patients will have inferior results before the cancer mainstream accepts hyperthermia as a relatively easy way of prolonging the lives of many patients.

References

Flinn R. Amgen halts pancreatic cancer trial after drug failure. Bloomberg.com. Aug 8, 2012.

Garassino MC, Martelli O, Bettini A, et al. TAILOR: A phase III trial comparing erlotinib with docetaxel as the second-line treatment of NSCLC patients with wild-type (wt) EGFR. 2012 ASCO Annual Meeting. J Clin Oncol. 30, 2012 (suppl; abstr LBA7501).

Glatter R. Drug shortages compromise emergency medical care. Forbes.com, April 11, 2012.

Ishikawa T, Kokura S, Sakamoto N, et al. Phase II trial of combined regional hyperthermia and gemcitabine for locally advanced or metastatic pancreatic cancer. Int J Hyperthermia. 2012 Jul 27.

Mehta M et al. Neoplasms of the central nervous system. In: DeVita et al. Cancer: Principles and Practice of Oncology. 9th ed. 2011.

Moss RW. Hyperthermia moves to fore as CAM treatment of cancer. Townsend Lett. January 2010.

Pollack A. Genentech wins approval for new breast cancer drug. New York Times. June 8, 2012.

Schrump DS et al. Non-small cell lung cancer. In: DeVita et al. Cancer: Principles and Practice of Oncology. 9th ed. 2011.

Wendling P. Docetaxel bests erlotinib in EGFR wild-type lung cancer. Elsevier Global Medical News. June 18, 2012. www.medconnect.com.au.

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.