Fwd: THE MOSS REPORTS Newsletter (03/21/04)

[Guest guest]

21 Mar 2004 20:00:06 -0000

" Cancer Decisions "

THE MOSS REPORTS Newsletter (03/21/04)

 

----------------------

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

Newsletter #125 03/21/04

----------------------

 

 

 

THE MOSS REPORTS

 

 

 

This week we begin a two-part discussion of the drug oxaliplatin, recently

approved by the FDA as a first line treatment for advanced colorectal cancer.

 

 

For most people, news about developments in the world of medicine comes in the

form of newspaper or TV items. The information given to the journalists who are

responsible for reporting on such developments is very often delivered at press

conferences paid for and publicized by the pharmaceutical industry, and 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

the treatment 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 offers the best 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 ONE

 

 

 

In the last few weeks I have discussed two new drugs, Eribtux and Avastin, both

of which have recently been approved by the US Food and Drug Administration

(FDA) for the treatment of advanced colorectal cancer. But no discussion of such

agents would be complete without also including oxaliplatin. This drug, which is

marketed as Eloxatin, was initially approved in 2002 for limited use in advanced

colorectal cancer where previous treatments had failed. Then, in January 2004,

the FDA extended the therapeutic scope for oxaliplatin by granting approval for

it to be used as a first-line treatment for metastatic colorectal cancer.

 

 

Oxaliplatin has been a meteoric success story for Sanofi-Synthelabo, the huge

French company that distributes it worldwide. Because physicians may legally

prescribe a drug in an 'off label' way (that is, they may give a drug to

patients in a way that has not yet received explicit FDA approval) oxaliplatin

had already cornered 40 percent of the advanced colorectal cancer market by the

time that FDA endorsed its use as a first-line treatment (Hovey 2004).

 

 

Oxaliplatin is one of the so-called platinum drugs; cisplatin and carboplatin

are other examples. Although the platinum drugs are widely used in the treatment

of many kinds of cancer, until the arrival of oxaliplatin they had not found a

place in the treatment of colorectal cancer. Instead, the standard of care for

decades has been a combination of 5-fluorouracil (5-FU) and leucovorin (LV).

With the advent of the drug irinotecan (also known as CPT-11, or Camptosar) the

Saltz regimen was born. This regimen, named after Leonard Saltz, MD, of Memorial

Sloan-Kettering Cancer Center in New York, combines 5-FU, LV and irinotecan, a

mixture that is often referred to as IFL. In 2001, clinical trials involving the

Saltz regimen were suspended because of several patient fatalities. (The

National Cancer Institute's website, explaining the suspension of these trials,

has the following to say about the Saltz regimen (IFL): " It appears that a

particular combination of irinotecan, 5-FU and LV --

known as the Saltz regimen -- has potentially lethal side effects. " ) With the

FDA's limited approval of oxaliplatin in 2002, a new approach to the

chemotherapy of metastatic colorectal cancer was developed, using oxaliplatin in

combination with the tried and tested 5-FU/LV - a mixture often referred to as

FOLFOX.

 

 

I understand that the names and combinations used in discussing this topic (such

as ILF and FOLFOX as well as IROX and FOLFIRI) can be dizzying. If you have

trouble keeping all them clear in your mind, don't be surprised. Even experts

find that the treatment picture for colorectal cancer to have become very

confusing, especially since the approval of Erbitux and Avastin. For nearly 40

years the treatment of advanced colorectal cancer meant mainly one thing: 5-FU

(with or without leucovorin). Now there are four new agents competing for the

same niche and the relative positions of these various agents and regimens is up

for grabs.

 

 

 

Effects of the Treatment

 

 

 

The key questions are these: What does oxaliplatin do to and for cancer

patients? Does it preserve or improve quality of life? And perhaps most

important of all, does it actually increase overall survival? In order to answer

these questions one must examine the drug's clinical track record by comparing

the studies that have been done and the articles that have been published

concerning the use of oxaliplatin in colorectal cancer.

 

 

There are currently over 850 articles on oxaliplatin in PubMed, the US

government's repository of medical citations, abstracts and links. Of these, 27

refer to randomized controlled trials (RCTs), the gold standard for assessing

the worth of new therapies. Among the 27 RCTs cited in PubMed there are only

half a dozen that yield genuinely new information to help us answer our

questions. Let us consider what the most relevant of these trials show about the

actual effects of oxaliplatin on patients with colorectal cancer, especially in

terms of how the drug affects their overall survival and quality of life.

 

 

The most positive news about oxaliplatin came in January 2004, when oncologist

Richard M. Goldberg, MD, and colleagues, of the University of North Carolina,

published a randomized controlled trial of three regimens for previously

untreated patients with metastatic colorectal cancer. These regimens were IFL

(the Saltz regimen), irinotecan and oxaliplatin (a regimen called IROX) and 5-FU

+ LV + oxaliplatin (dubbed FOLFOX). In this trial, the median survival time was

15.0 months with IFL, 17.4 months with IROX and 19.5 months with FOLFOX. Thus,

there appeared to be a 4.5 month advantage to the FOLFOX regimen over IFL.

 

 

Dr. Goldberg and his colleagues also concluded that the patients on the FOLFOX

regimen " had significantly lower rates of severe nausea, vomiting, diarrhea,

febrile neutropenia, and dehydration " than did patients on the other regimens

(Goldberg 2004). These are the most positive conclusions that have been

published concerning the use of oxaliplatin. This study seems to indicate that

oxaliplatin adds several months to the overall survival of patients with

advanced colorectal cancer, at least compared to the other standard chemotherapy

regimens.

 

 

Not so, say defenders of the Saltz regimen. " First‚ 5-FU was administered in a

different fashion in both regimens‚ " according to Dr. Neil J. Meropol director

of the Gastrointestinal Cancer Program at the Fox Chase Cancer Center‚

Philadelphia. Patients on FOLFOX had access to CPT-11 as a backup if their

treatment failed. But very few people on IFL had access to FOLFOX if their

treatment was not successful. In fact, said Dr Saltz himself, three times as

many people got second-line treatment with CPT-11 when FOLFOX failed, " ...so

researchers cannot say yet with certainty why people on FOLFOX lived longer "

(McCarthy 2002).

 

 

Yet other studies, such as one carried out in France and published in the

Journal of Clinical Oncology in 2000 (Giacchetti) tell a different and more

complicated story. In this French study, 200 patients were treated with 5-FU and

LV, the standard drugs for metastatic colorectal cancer. But half of these

patients were randomly assigned to also receive oxaliplatin. Sixteen percent of

the patients receiving just 5-FU and LV had an objective response (i.e. partial

tumor shrinkage for one month or more) vs. 53 percent of those receiving the

additional oxaliplatin. That represents a more than a threefold difference in

oxaliplatin's favor, and at first sight this seems to confirm the impression

that oxaliplatin genuinely benefits patients.

 

 

The average (median) progression-free survival time was 6.1 months with 5-FU/LV

vs.7 months with oxaliplatin, which amounts to a gain of about one month.

However, it would be a mistake to think that " progression-free survival "

necessarily means that patients live longer. That question is only addressed by

the overall survival figures, which record when people die of any causes

(including side effects of the treatment). A truly startling finding of this

study was that the average (median) overall survival time was 19.9 months with

the standard regimen vs. 19.4 months when oxaliplatin was added. In other words,

those who received oxaliplatin actually seem to have had their lives SHORTENED

by some weeks (Giacchetti 2000). One cannot help noting that negative findings

such as this are very often ignored in the rush to approve new, and potentially

profitable, agents. Only positive findings are deemed worthy of further

development and publicity.

 

 

In August 2000 the Journal of Clinical Oncology also published another

randomized trial of 5FU/LV with or without the addition of oxaliplatin, as a

first-line treatment in metastasized but as yet untreated advanced colorectal

cancer (de Gramont 2000) - its newly expanded indication. In this case, 420

patients received an intensified form of the 5-FU/LV regimen. Patients who

received oxaliplatin in addition to the standard regimen had almost three months

longer progression-free survival (median, 9.0 v 6.2 months, which was

statistically significant). Again, there was promising news on the shrinkage

front: in the oxaliplatin group the partial response rate was double that of the

control group (50.7 v 22.3 percent). However, the improvement in overall

survival was just six weeks and did not reach statistical significance; that is,

it may simply have been due to chance.

 

 

Other studies, too, have come to less positive conclusions than the Goldberg

clinical trial. In 2001, a medical group in Argentina compared oxaliplatin alone

to oxaliplatin plus the standard regimen as the first-line treatment for

metastatic colorectal cancer patients. Seventy-three patients were randomized to

receive either oxaliplatin or oxaliplatin plus the standard regimen. The

objective response rate was 9 percent in the oxaliplatin arm vs. 45 percent in

the oxaliplatin plus standard treatment arm. This is an astonishing difference,

which shows how much more active oxaliplatin is when used in combination with

the standard drugs (Zori Comba 2001).

 

 

The median progression-free survival was 2 months in the oxaliplatin arm vs. 3.9

months in the combination arm, again nearly double. (There was no report on

overall survival.) But, again, there was a steep price to pay: serious to severe

neutropenia (white blood cell count depression) was seen in 23 percent of

patients in the combination arm vs. none in the oxaliplatin-alone arm. Two

patients died as a result of treatment, both of them in the combined-treatment

arm. In the combined-treatment arm, severe diarrhea was seen in 34 percent,

severe vomiting in 14 percent and severe mouth sores (stomatitis) in 14 percent

of patients.

 

 

The authors concluded that while oxaliplatin had limited activity in metastatic

colorectal cancer, the combination was " unfeasible due to a high level of

myelosuppression and gastrointestinal toxicity " (Zori Comba 2001). This was one

of the few clinical trials to draw an essentially negative lesson from such

results. Most clinical studies of new pharmacological agents (especially

American studies) conclude with positive recommendations whenever possible,

regardless of the effect on quality of life.

 

 

Perhaps the last word belongs to Sanofi-Synthelabo, the drug's manufacturer. At

its www.eloxatin.com website I found this terse (and disarmingly candid)

statement: " No results are available at this time that demonstrate a clinical

benefit, such as improvement of disease-related symptoms or increased survival "

for oxaliplatin given alone or in combination. So there we have it: the

manufacturer states that oxaliplatin has not been shown to confer lasting

clinical benefit - and yet the drug has become a top-seller.

 

 

 

Neoadjuvant Treatment

 

 

 

One potentially useful possibility, raised as a result of two retrospective case

series, is that the combination of oxaliplatin and 5-FU/LV may be able to shrink

metastases sufficiently to permit surgery, thereby increasing 5-year survival to

between 28 percent and 34 percent. This is called " neoadjuvant

treatment " -chemotherapy given for the purpose of making surgery more feasible or

successful. I have seen British estimates that indicate that up to 11 percent of

all advanced colorectal cancer patients potentially fall into this category. On

the whole, retrospective studies do not form a reliable basis for treatment

decisions but this option is certainly worth further investigation in rigorous

clinical trials. (There are presently four clinical trials examining precisely

that question.)

 

 

However there is reason to doubt that this option will benefit many people. At

www.eloxatin.com, Sanofi reports preliminary data from a multicenter,

randomized, three-arm controlled study conducted in the US and Canada. (It is

cited under the title " Combination therapy with Eloxatin and infusional 5-FU/LV

in previously treated patients with advanced colorectal cancer. " ) There were 821

patients in this study, all of whom had relapsed or progressed within 6 months

of first-line therapy with 5-FU/LV and irinotecan. No patients had a complete

response in any category and only 9 percent (13 out of 152 patients) had a

partial shrinkage in the combined treatment category. It is from this pool of

responding patients that candidates for further surgery would have to be found.

So the actual number of beneficiaries would, logically, be a fraction of that 9

percent.

 

 

In Britain, the National Institute for Clinical Excellence (NICE), which

oversees the selection of drugs for use by medical practitioners within the

National Health Service, tried to limit the use of oxaliplatin to this

statistically minor indication. They were promptly assailed in a mass

circulation newspaper (the Daily Telegraph) by a group of 28 oncologists, eager

to testify that the Institute was putting money above lives. This sort of

argument is always an explosive one to use on the general public. One oncologist

even claimed that oxaliplatin, used in combination, would " triple the median

survival time " (Dyer 2002). Not surprisingly, the NICE decision was recently

overturned in the courts on an appeal from a powerful combination of Big Pharma

and British oncologists. In the US, we do not even have a watchdog group such as

NICE which can decide whether particular drugs are a good investment of the

public's increasingly scare health care dollars. Is it any wonder that the cost

of

health care, and particularly of new pharmacological agents, is spiralling out

of control?

 

 

 

Side Effects of Oxaliplatin

 

 

 

Originally, new forms of platinum drugs were developed in an attempt to avoid

the well-known and sometimes drastic side effects of cisplatin. I remember

debating an oncologist in Indianapolis, Indiana, in 1990, who assured me and our

television audience that the newly developed carboplatin was without the nasty

side effects of its sister compound, cisplatin. However, it turned out that the

side effects of all platinum compounds, including carbo- and oxaliplatin, are

many, varied, and occasionally extreme. According to Sanofi, 99 percent of

patients getting the combination treatment experienced side effects and 73

percent had moderate to severe (NCI Grade 3/4) side effects. (That's up from 41

percent in those who receive just 5-FU/LV).

 

 

Oxaliplatin commonly causes peripheral neuropathy, which is numbness or tingling

in the fingers, toes, neck or throat. According to the manufacturer, when

oxaliplatin is given in combination with 5-FU/LV, acute neuropathy is seen in a

majority (56 percent) of patients. Websites directed at the public tend to

depict side effects as tolerable, short-term and reversible. However, this

oxaliplatin-induced neuropathy has actually proved to be long-term in 48 percent

of patients. The company describes the problem thus: " persistent (greater than

14 days), primarily peripheral, sensory neuropathy that …may also include

deficits in proprioception [the neurological perception of balance and spatial

position, ed.] that can interfere with daily activities (e.g. writing,

buttoning, swallowing, and difficulty walking from impaired proprioception). "

 

 

For some people, these symptoms are exacerbated by exposure to cold things, such

as iced drinks or cold air. Patients are told: " Cover your skin if you must go

outside in cold temperatures. Do not drink cold drinks or use ice cubes in

drinks. Do not put ice or ice packs on your body… " The company even cautions

patients: " Do not breathe deeply when exposed to cold air. "

 

 

As noted above, myelosuppression (a reduction in the production of blood cells

in the bone marrow) is also a common side effect of treatment with oxaliplatin.

Myelosuppression can result in various clinical blood conditions. Anemia is seen

in 81 percent, leukopenia in 76 percent, neutropenia in 73 percent and

thrombocytopenia in 64 percent. The general result is bruising or bleeding,

fatigue, and an increased risk of infection. (Not surprisingly, fatigue and

general malaise are seen in almost 70 percent of patients).

 

 

Diarrhea, nausea and vomiting are routinely encountered while taking

oxaliplatin, and while some of the more severe episodes can be controlled by

medications, these side effects are nonetheless debilitating and distressing.

 

 

The side effects of the treatment may also sometimes be life-threatening. Nine

percent of patients on the combination suffered blood clots (thromboembolism)

and eight percent had chest pain. In fact, 18 percent of all patients in the

infusional 5-FU/LV arm had to discontinue treatment because of adverse effects

related to gastrointestinal or blood adverse events, or neuropathies. The

company's own package insert states that " incidence of death within 30 days of

treatment, regardless of causality, was 5 percent with the Eloxatin and

infusional 5-FU/LV combination, 8 percent with Eloxatin alone, and 7 percent

with infusional 5-FU/LV. " It continues: " Of the 7 deaths that occurred on the

Eloxatin and infusional 5-FU/LV combination arm within 30 days of stopping

treatment, 3 may have been treatment related, associated with gastrointestinal

bleeding or dehydration. " This goes unmentioned in most of the promotional

stories one finds on this treatment.

 

 

 

Less Common Side Effects

 

 

 

Oxaliplatin has some less common side effects, too. For example:

 

 

Laryngeal spasm. The muscles that control the larynx (voice box) may be

affected, resulting in difficulty in swallowing and severe breathing problems.

Exposure to cold is often a trigger.

 

 

Allergic reactions. Signs include skin rashes and itching, a high temperature,

shivering, facial redness, dizziness, headache, breathlessness and anxiety.

 

 

Sore mouth and taste change. The patient's mouth may become ulcerated and sore.

Food may taste different or strange. One patient described the taste changes

that accompany chemotherapy in this way: " I find so many of the foods I used to

love are now repulsive. …This scares me more than the cancer. I always liked to

eat, now I'm avoiding meals in any way I can " (Johnston 2000).

 

 

 

Coping with Side Effects

 

 

 

According to the Dr. Aimery de Gramont, one of the developers of oxaliplatin,

the drug's side effects " did not result in impairment of quality of life, " a

statement I find difficult to comprehend in the light of the manufacturer's own

data. These French authors conclude that the 5-FU-LV-oxaliplatin combination

" seems beneficial as first-line therapy in advanced colorectal cancer,

demonstrating a prolonged progression-free survival with acceptable tolerability

and maintenance " of quality of life (de Gramont 2000). However, what is

'acceptable' to doctors may not be so to patients and their families, especially

once they realize the lack of impact these drugs have on survival in most cases.

 

 

Meanwhile, for most patients the possibility of achieving a partial and

temporary shrinkage comes at a high price, both literally and figuratively. The

cost of treatment runs to approximately $15,000 per patient for the combination

(£9,216 in Great Britain {Nicholls 2001}). Oxaliplatin alone, it is said, costs

seven times as much as the standard therapy with 5-FU and LV (Dyer 2002).

 

 

(To be concluded, with references, next week.)

 

 

 

 

--Ralph W. Moss, PhD

 

 

---------------

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.

 

--------------

 

IMPORTANT NOTICE:

 

 

Please do not REPLY to this letter. All replies to this email address are

automatically deleted by the server and your question or concern will not be

seen. If you have questions or concerns, use our form at

http://www.cancerdecisions.com/contact.html

Thank you.

 

 

 

To SUBSCRIBE TO OUR FREE NEWSLETTER: Please go to

http://cancerdecisions.com/list/optin.php?form_id=8

and follow the instructions to be automatically added to this list.

Thank you.

 

=====

 

 

 

 

 

Finance Tax Center - File online. File on time.