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" Cancer Decisions "

THE MOSS REPORTS Newsletter (03/28/04)

 

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Ralph W. Moss, Ph.D. Weekly CancerDecisions.com

Newsletter #126 03/28/04

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THE MOSS REPORTS

 

 

This week we conclude our two-part discussion of the drug oxaliplatin, a drug

that was recently approved by the FDA as a first line treatment for advanced

colorectal cancer.

 

For most of us, articles in the newspapers or items on TV are our principal

source of information about developments in the world of medicine. However, the

journalists who compose such news items more often than not gather their

information at press conferences paid for and publicized by the pharmaceutical

industry. It is rare indeed for anything but the most positive picture to emerge

from presentations of this kind.

 

At the Moss Reports we have made it our life's work to examine emerging

treatments with a critical and impartial eye. While we earnestly hope for a

breakthrough in the long (and so far largely fruitless) war on cancer, we remain

solidly committed to the philosophy that we have termed 'friendly skepticism' -

that is, the principle of evaluating new treatments not by what we wish they

could be, but by what the science and the clinical evidence actually prove that

such treatments can - and cannot - do.

 

We extend this principle to the writing of the Moss Reports that we publish on

200-plus different types of cancer. Each report offers a thorough, in-depth

review of the most useful conventional and alternative treatments for a

particular kind of cancer. For cancer patients and their families, a Moss Report

can prove to be an invaluable tool in the struggle to assemble a treatment plan

that incorporates the best options from both standard and complementary

medicine.

 

To order a Moss Report, or to schedule a phone consultation with Dr. Ralph Moss,

please call Diane at 1-800-980-1234 (814-238-3367 when calling from outside the

US). You can also order reports through our website,

http://www.cancerdecisions.com

 

 

HOW EFFECTIVE IS OXALIPLATIN? PART TWO

 

 

Last week I began a discussion of the recent FDA approval of the drug

oxaliplatin as a front-line treatment for advanced colorectal cancer. I conclude

that discussion this week.

 

 

Glutathione to the Rescue

 

 

As I have previously reported, oxaliplatin-induced nerve damage has been well

known since the early clinical trials of this drug. Interestingly, the side

effects of oxaliplatin may be reduced if the patient also takes the antioxidant

glutathione, a natural compound that consists of three amino acids.

 

Scientists in Italy conducted a study to evaluate the neuroprotective effects of

glutathione in patients receiving oxaliplatin (Cascinu 2002). Some colorectal

cancer patients were given oxaliplatin and glutathione. Others received

oxaliplatin and a placebo (in this case an injection of saline). By the eighth

cycle of the drug, 15 of the 19 patients (78.9 percent) who received the placebo

plus oxaliplatin had nerve damage (neurotoxicity) compared to just 9 of the 21

patients (42.9 percent) who received oxaliplatin plus glutathione. For serious

to severe (grade 2-4) neuropathy, there was an even greater difference: while 11

of 19 patients (57.9 percent) in the oxaliplatin-plus-placebo group experienced

neuropathy, only 2 of 21 (9.5 percent) experienced neuropathy in the

oxaliplatin-plus-glutathione group, a six-fold reduction. After a full 12

cycles, serious to severe nerve damage was seen in 8 of 19 patients (42.1

percent) in the oxaliplatin-plus-placebo group, compared to 3 of 21

patients (14.3 percent) in the group receiving glutathione. These differences

were all statistically significant.

 

Oncologists frequently argue that while concurrent use of antioxidants might

reduce treatment-related side effects, it also runs the risk of reducing the

cancer fighting power of chemotherapy. But in this study the addition of

glutathione to the regimen did not reduce the effectiveness of chemotherapy;

indeed, it yielded a response rate equal to that of conventional treatment. The

overall response rate was 23.1 percent in the placebo-added group compared to

26.9 percent in the glutathione-added group.

 

The authors of this study concluded that glutathione is " a promising drug for

the prevention of oxaliplatin-induced neuropathy " and that " it does not reduce

the clinical activity of oxaliplatin. " In other words, it is now known that by

injecting a single, nontoxic antioxidant, glutathione, doctors can safely and

dramatically reduce the nerve damage that occurs as a side effect of

chemotherapy with oxaliplatin. Despite this, the use of glutathione does not

seem to have caught on among conventional oncologists, who remain steadfastly

hostile to antioxidants being used concurrently with chemotherapy.

 

To order glutathione click or go to:

http://www.amazon.com/exec/obidos/ASIN/B00014EALA/cancerdecisio-20/103-4018872-4\

386244

 

 

Perils of Accelerated Approval

 

 

While it is true that oxaliplatin sometimes dramatically increases the

percentage of tumors that shrink, and may increase progression-free survival, it

has not been consistently shown to prolong overall survival in most studies. (As

I discussed in last week's newsletter, the Goldberg trial with FOLFOX is an

exception.) In this, oxaliplatin is similar to several other drugs (such as

Erbitux) that have recently gained accelerated FDA approval for use in treating

advanced cancers. Such accelerated approval, buoyed by industry publicity,

journalistic hyperbole and the sometimes indiscriminate enthusiasm of the

oncology profession, promotes the idea that we are making substantial progress

in the war on cancer. This is a myth that serves the interests of many within

the medical profession and the pharmaceutical industry, as well as certain

government officials, while doing nothing to further the interests of patients.

The usefulness of drugs that have been fast-tracked in this way is

usually exaggerated and the public is rarely told that these drugs at best

extend the lives of cancer patients only by a couple of months. During that time

patients are often subjected to side effects that vitiate the pleasure they

might otherwise have taken in spending quality time with their loved ones.

 

Even Dr. Leonard Saltz, himself one of the resolute optimists, has cautioned

that he does not see a cure for colorectal cancer on the horizon. " Instead‚ " he

has said, " what we have done over the past decade‚ and what I believe we will

continue to do at an accelerated pace‚ is come up with new drugs that provide

modest advantages and modest steps forward. "

 

Fortune magazine's March 22, 2004, issue (available only this week at

newsstands) has an extremely interesting article by Clifton Leaf on the war on

cancer and why we are losing it. You can read an excerpt from it, and obtain a

reprint, by clicking or going here:

http://www.fortune.com/fortune/articles/0,15114,598425,00.html

 

I realize that taking a critical stand on new chemotherapeutic agents can stir

up many negative emotions. Patients and their loved ones have often placed their

last hopes on these treatments, and have made a deep commitment to the

possibility of success. Those who feel they are doing well on a particular

treatment may resent any talk of side effects or drawbacks. For others, such

criticism is a bitter reminder of their treatment's toxicity and its ultimate

failure. This sometimes generates deep hostility towards the doctors who gave

the treatment.

 

I criticize American oncologists for operating what the New York Times calls a

" chemotherapy concession, " wherein they are financially rewarded for giving more

expensive drugs (Abelson 2003). The Journal of the National Cancer Institute

(JNCI) has commented that " private-practice oncologists typically derive

two-thirds of their income from selling chemotherapy " (Reynolds 2001). This

makes them financially dependent on increasing the acceptance and sale of

expensive chemotherapeutic agents. They thereby have become the junior partners

of the pharmaceutical companies rather than independent advocates for their

patients' interests, economic as well as medical. To put it politely, this

situation is not conducive to making impartial treatment decisions. It also

undermines the public's confidence in any positive statements made by the

medical profession concerning the merit of chemotherapeutic drugs.

 

To read the New York Times editorial concerning the " chemotherapy concession " ,

click or go to: http://www.nytimes.com/2004/03/22/opinion/22MON2.html

 

On the other hand, we should remember that oncologists are faced with an uphill

struggle. They are trying their hardest, using the tools available to them, and

can perhaps be forgiven for feeling beleaguered when they are questioned sharply

about the safety and effectiveness of their methods. It is also understandable

that oncologists tend to see a glimmer of hope where others see only very bleak

statistics.

 

If we are to arrive at real knowledge of what truly works against cancer,

however, we must at least agree on the criteria for success. I often find myself

at odds with the oncology profession over this. Publications on chemotherapy

generally focus on what are called " surrogate endpoints. " These are tests that

measure the success of a treatment not by whether, or how much, it really

benefits the patient, but in terms of how it affects some other parameter, such

as a biochemical marker or blood test. Usually it turns out that this marker has

little to tell us about durable, real world benefits to patients.

 

Even when a drug temporarily shrinks a tumor, or prolongs the interval of

progression-free survival, as oxaliplatin appears to do, we need to carefully

examine the practical relevance to the patient of such temporary interruptions

in the course of the disease. While surrogate end points may give patients the

feeling that progress is being made, they are in reality both transient and of

dubious significance.

 

Why do I say that such shrinkages are of little significance? Isn't it

self-evidently a good thing to shrink a tumor or to delay its inexorable forward

progression? Not necessarily. For example, imagine a situation in which the

tumor shrinks but the patient's health is concurrently undermined by the

toxicity of the treatment. He or she may suffer and die of treatment-related

causes rather than as a direct result of the cancer. And, in fact, as I

mentioned last week, oxaliplatin-containing regimens have resulted in

treatment-related deaths in clinical trials. Another possibility is that the

disease may accelerate more rapidly after a progression-free period. In either

case, the patient may die at approximately the same point, or even earlier, than

if he or she had had no treatment at all.

 

For these, and other, reasons, most biostatisticians look to improved overall

survival as the only real criterion of success for a treatment. The

aforementioned Goldberg study is promising in this regard. However, we must also

inquire carefully into the quality of life during that period of prolonged

survival. What sort of existence are we really creating for patients? Will it be

a time for peaceful reflection, a time for reconnecting with family and friends?

Or will it instead be a period of additional pain and turmoil, of horrendous and

even life-threatening symptoms, taking place in an impersonal medical setting?

 

The temporary shrinkage of a tumor, or even some additional weeks of survival,

can come to seem rather meaningless in this context. A colorectal cancer patient

wrote to me recently that " from a patient's point of view I can tell you that

shrinkage at any point during treatment is such an incredible blessing that you

feel the ten grand a month [the price of some new drugs, ed.] is easily

justified. " But he quickly added, " In the midst of a battle you easily lose

sight of the war. "

 

 

 

--Ralph W. Moss, PhD

 

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References

 

 

Abelson, Reed. Drug sales bring huge profits, and scrutiny to cancer doctors.

New York Times. January 26, 2003, page A1.

 

Cancer scare tactics: New York Times editorial March 22, 2004

http://www.nytimes.com/2004/03/22/opinion/22MON2.html

 

Cascinu S, Catalano V, Cordella L, et al. Neuroprotective effect of reduced

glutathione on oxaliplatin-based chemotherapy in advanced colorectal cancer: a

randomized, double-blind, placebo-controlled trial. J Clin Oncol. 2002 Aug

15;20(16):3478-83.

 

Cunningham D, Falk S, Jackson D. Clinical and economic benefits of irinotecan in

combination with 5-fluorouracil and folinic acid as first line treatment of

metastatic colorectal cancer. Br J Cancer 2002 Jun 5;86(11):1677-83.

 

de Gramont A, Figer A, Seymour M, et al. Leucovorin and fluorouracil with or

without oxaliplatin as first-line treatment in advanced colorectal cancer. J

Clin Oncol. 2000 Aug;18(16):2938-47.

 

Dyer, Owen. Oncologists protest about NICE's decision on cancer drugs. British

Medical Journal 2002;324:1413 (15 June). Retrieved March 12, 2004 from:

http://bmj.bmjjournals.com/cgi/content/full/324/7351/1413

 

Giacchetti S, Perpoint B, Zidani R, Le Bail N,. et al. Phase III multicenter

randomized trial of oxaliplatin added to chronomodulated fluorouracil-leucovorin

as first-line treatment of metastatic colorectal cancer. J Clin Oncol. 2000

Jan;18(1):136-47.

 

Goldberg RM, Sargent DJ, Morton RF, et al. A randomized controlled trial of

fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in

patients with previously untreated metastatic colorectal cancer. J Clin Oncol.

2004 Jan 1;22(1):23-30.

 

Hovey, Hollister H. 3rd Update: FDA OK's Genentech's Colon Cancer Drug Avastin.

Thursday, February 26, 2004 05:59 PM ET. Dow Jones Newswires. Retrieved March 8,

2004 from:

http://www.quicken.com/investments/news_center/story/?story=NewsStory/dowJones/2\

0040226/ON200402261759001254.var & column=P0DFP

 

Johnston Lorraine. Colon & Rectal Cancer: A Comprehensive Guide for Patients &

Families, Chapter 11 O'Reilly & Associates, Inc., 2000. Retrieved March 11, 2004

from:

http://www.patientcenters.com/colon/news/side_effects.html.

 

Kidani Y, Noji M, Tashiro T. Antitumor activity of platinum(II) complexes of

1,2-diamino-cyclohexane isomers. Gann. 1980 Oct;71(5):637-43.

 

Nicholls C, Cassidy J, Freemantle N, Harrison M, Carita P. Cost-effectiveness of

combination chemotherapy (oxaliplatin or irinotecan in combination with 5-FU/FA)

compared with 5-FU/FA alone. Journal of Medical Economics, 2001;4:115-125.

 

Leaf, Clifton, The War on Cancer. Fortune, March 22, 2004

http://www.fortune.com/fortune/articles/0,15114,598425,00.html

(Online version requires subscription; reprints available.)

 

McCarthy, Alice. New chemotherapy drugs and new targeted therapies are giving

patients combined choices for treating colon cancer. Cure, 2002. Retrieved March

11, 2004 from:

http://www.curetoday.com/backissues/v1n4/feature/colon/

 

Piccart MJ, Green JA, Lacave AJ, Reed N, Vergote I, Benedetti-Panici P, Bonetti

A, Kristeller-Tome V, Fernandez CM, Curran D, Van Glabbeke M, Lacombe D, Pinel

MC, Pecorelli S. Oxaliplatin or paclitaxel in patients with platinum-pretreated

advanced ovarian cancer: A randomized phase II study of the European

Organization for Research and Treatment of Cancer Gynecology Group. J Clin

Oncol. 2000 Mar;18(6):1193-202.

 

Reynolds T. Salary a major factor for academic oncologists, study shows. J Natl

Cancer Inst 2001;93(7):491. Retrieved March 12, 2004 from:

http://jncicancerspectrum.oupjournals.org/cgi/content/full/jnci;93/7/491

 

Zori Comba A, Blajman C, Richardet E, A randomised phase II study of oxaliplatin

alone versus oxaliplatin combined with 5-fluorouracil and folinic acid (Mayo

Clinic regimen) in previously untreated metastatic colorectal cancer patients.

Eur J Cancer. 2001 May;37(8):1006-13.

 

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IMPORTANT DISCLAIMER

 

The news and other items in this newsletter are intended for informational

purposes only. Nothing in this newsletter is intended to be a substitute for

professional medical advice.

 

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