DIY Research Guide

Page 1


THE MOSS REPORT DO-IT-YOURSELF RESEARCH GUIDE

Table of Contents

THE UNVARNISHED TRUTH

NCCN GUIDELINES FOR PROFESSIONALS

NCCN GUIDELINES FOR PATIENTS

PDQ

THE DEVITA TEXTBOOK

UPTODATE.COM

3-MONTH REGIMENS

GOOGLING FOR ANSWERS

LIMITATIONS OF CLINICAL TRIALS

POTENTIAL CONFLICTS OF INTEREST

PROBLEMS WITH CLINICAL TRIALS

SUMMATION

A PERSONAL NOTE

THE UNVARNISHED TRUTH

Many cancer patients, by some accounts up to 90%, simply take their doctor ’s advice about the proper treatment of their disease. They do not seek a second opinion or check out their treatment options. The main reason for this attitude is fear:

● Fear of the disease

● Fear of delaying urgent treatments

● Fear of angering doctors

● Fear of the bad news they might find on the internet

But the fact that you are reading this guide means that you are probably in a select 10% minority:

● You are looking for accurate information on your condition.

● You want the unvarnished truth.

● You want to understand what you ’ve got, and the next steps to take.

● You are seeking to keep major decisions under your control . It may sound strange to put the words “cancer ” and “DIY ” (do -it-yourself ) in the same sentence. So let ’s be clear. We are not suggesting that you treat yourself with tools purchased at The Home Depot! Of course, you need professional medical help. But we do suggest that you learn to research your cancer so that you and your doctor can make the best decisions possible. That ’s what we mean by DIY.

TRUST, BUT VERIFY

Some people, when they get a cancer diagnosis, just hang a “Gone Fishing ” sign on their brains. They turn over ever y important decision to their doctors.

Others make the opposite mistake. They disbelieve anything coming from the “Cancer Establishment,” even things that are based on good evidence.

Each of these extreme positions is unhelpful , but each contains a kernel of truth. We need to trust our doctors. But we also need to remain skeptical about all debatable claims. A good motto is “ Trust, But Verif y. ”

Trust your doctors, for sure. But also check up on their education and achievements, the safety record of their hospitals, and especially their treatment recommendations.

There are too many cases of the medical profession making serious errors. These have had devastating effects on patients. As one example, a few decades ago many women (my wife included) were prescribed the hormonal drug DES to prevent miscarriages during their pregnancies. This resulted in instances of GYN cancer for the so - called “DES daughters” of the next generation.

A report from Johns Hopkins University showed that ever y year more than 250,000 people in the U.S. die from medical errors. Other reports claim that number is as high as 440,000! Either way, “Medical Error ” is the third leading cause of death in the U.S., just behind heart disease and cancer.

We don’t want that to happen to you! So in this DIY guide we will show you how to protect yourself and your family from misjudgments and bring about the best possible outcome of your treatment. We want to help you research the safest and most effective treatments of your own cancer. You can learn the best options. You can know what to expect, both positive and negative.

THE DIAGNOSIS

When you are told you have cancer, you need to establish the exact diagnosis. Diagnosis is the process of identif ying a disease or condition from its signs and symptoms. At the ver y least, you need to know the exact

location of the tumor, the stage (severity of the disease), the grade (degree of abnormality of the cells), as well as any individual characteristics (such as major genetic mutations). All of these things may affect the proper treatment decisions.

Errors can occur in this process of evaluation. So you are well within your rights to request a second or even a third opinion on your original diagnosis. U.S. Medicare and other insurance plans cover a second opinion when a doctor is recommending surger y or any other major procedure.

Before considering any “alternative treatments,” which abound on the internet, you need to learn the pluses and minuses of the standard treatment options for your disease.

BASIC PRINCIPLES OF RESEARCH

In this DIY guide, we show you how to fully inform yourself about the standard treatment of your disease. You will then be better able to discuss treatments with your physicians and family.

But where to begin? Cancer is complex. There are more than 100 different types. Each of these is normally divided into four stages, ranked in order of severity. Most stages also have substages. For example, stage 3 cancer patients are usually further classified as low-, medium-, and high-risk cases, designated 3A , 3B, and 3C. All told, this makes for more than a thousand treatment situations that could be used to illustrate the basic principles of research.

In addition, there are four main treatment modalities: surger y, radiation, chemotherapy, and immunotherapy. This is not to mention “alternative” treatments. If we tried to take on the whole of cancer treatment, we would need thousands of pages of discussion. And as a matter of fact, a recent edition of the DeVita cancer textbook contains 2,432 pages, and weighs in at 9.8 pounds!

To illustrate the best DIY research methods we obviously need to narrow the search. So in this report, we will focus on a single treatment. Of a single stage. Of a single type of cancer. In what follows, we highlight that one situation, the chemotherapy of stage 3 colon cancer.

HINT: This will be our test case. But bear in mind that the research methods in this DIY guide are applicable to all kinds of cancer.

STAGE 3 COLON CANCER

Let ’s start with a ver y brief description of this test case. There are about 100,000 new cases of colon cancer in the U.S. each year. In fact, colon (or colorectal) cancer is the third leading cause of cancer deaths in the industrialized world. It is a malignant growth that arises in the large intestines, or bowel , the tube -shaped organ of digestion in the abdomen. Early forms of colon cancer are designated as stages 1 or 2. These have not invaded the bowel deeply and usually can be treated with surger y alone.

But nearly one - quarter of colon cancers are classified as stage 3 at the time they are found. That means that they have invaded the wall of the bowel , left small deposits, or involved nearby lymph nodes. Most doctors are convinced that stage 3 patients require aggressive chemotherapy (chemo) after surger y.

HINT: Stage 3 cancer is sometimes written as Stage III or Dukes’ Stage C. In this DIY guide, We have changed all mentions of these to a uniform “Stage 3.”

SEEING THE MEDICAL ONCOLOGIST

If you are diagnosed with stage 3 cancer you will be sent to see a surgeon and an oncologist. (If you are not, there may be something wrong!) You may not like doing this, but at least hear them out. Medical oncologists are usually well-trained and act professionally. The government goes to great lengths to prevent irresponsible behavior. Not only do they have to complete a three -year fellowship, but they are required to pass periodic exams to keep

up their license. But, despite all this, errors can occur. You may be offered a too harsh treatment when a milder one would do. Both you and the cancer doctor need to discuss all the options. That is the purpose of this DIY guide.

Now we want to introduce you to four online resources that will explain your main treatment options in an accurate way. These sites were all designed with doctors in mind. But they can also be used by inquisitive patients.

FOUR MAIN SOURCES

These four major sources of information are:

1. The National Comprehensive Cancer Network (NCCN). Like some of the others, this has both Professional and Patient sections.

2. The PDQ system of the National Cancer Institute (PDQ)

3. The DeVita , Hellman, and Rosenberg textbook, Cancer (DeVita)

4. UpToDate.com, an online medical information ser vice (UpToDate)

FIVE OTHER SOURCES

Before we cover these four main sources in depth, though, we want to say a few words about five other essential tools of online medical research. These are:

1. PubMed.gov

2. ASCO.org

3. NCI Dictionar y of Cancer Terms

4. Drugs.com

5. U.S. News & World Report ’s Hospital Ranking

www.themossreport.com

1. PUBMED.GOV Ever yone serious about DIY research should become familiar with PubMed. This is the U.S. National Librar y of Medicine’s database of 28 million medical journal articles. One can double - check primar y references there. It is always better to read the full text of an article than just the abstract. (Abstracts are sometimes misleading if they omit crucial facts or gloss over undesirable findings.) Increasingly, these days one has “open access” to free full texts online.

2. ASCO.ORG Another important resource is ASCO.org , especially its searchable Meeting Librar y. This site contains many presentations from the American Society of Clinical Oncology (ASCO) meetings. Some of these are published at the ASCO.org website before being published in medical journals. The interpretive articles in their newsletter, the ASCO Post, can also be ver y informative.

3. NCI DICTIONARY OF CANCER TERMS This dictionar y consists of over 8,000 terms related to cancer compiled by the National Cancer Institute (NCI). You can use it to define uncommon medical words and phrases. In this DIY guide, when we introduce an unusual term, we usually link it to a fuller definition in the NCI Dictionar y.

4. DRUGS.COM This free website has both a professional and a patient version. Both are excellent. The Drugs.com editorial team is comprised of six registered pharmacists and two physicians. We have found this site to be a no -holds-barred source of information on the side effects of drugs.

5. U.S. NEWS AND WORLD REPORT This magazine maintains a ver y useful Ranking of Best Hospitals for Cancer. You can use this to learn about both the reputational score and safety record of numerous U.S. hospitals. Treatment outcomes are usually better at top -rated hospitals. In such places, patients may also experience fewer infections or other preventable complications of treatment.

RISK OF RECURRENCE

Now on to a consideration of our test case. For over a centur y, colon cancer patients were offered surger y as their only treatment choice. But, while surger y became safer and more effective as the years progressed, it soon became clear that after surger y stage 3 patients were still in danger. A surgical “resection” may have appeared complete, but invisible nests of cancer cells were often left behind. Patients were still at considerable risk of their cancer recurring .

HINT: The first recorded operation for colon cancer was performed by Jean Francis Reybard , MD, of Lyon , France, in 1823. By the early 20th centur y, the operation had become fairly common , but the death rate from surger y was 37%. Surger y remained the only treatment until the first clinical trial confirmed the effectiveness of the drug 5-FU in 1990.

How great a risk is depends on a number of factors. The main one is the degree to which cancer had penetrated the bowel wall at the time of the operation. Another is the number of affected lymph nodes. The specific location of the tumor (e.g ., on the left or right side) can also influence the odds of a relapse.

A 2014 study from Japan showed that stage 3 colon cancer patients who received no treatment after surger y had about a 40% chance of their cancer recurring within three years of surger y. But high-risk stage 3C patients had about an 80% chance of a relapse. So clearly something further needs to be done for these patients.

5-FU, OX, AND FOLFOX

That ‘something , ’ for most oncologists, is chemotherapy. In 1990, Charles Moertel , MD, of the Mayo Clinic showed that chemotherapy could reduce the chance of a recurrence in stage 3 colon cancer. In most of the industrialized world, doctors now recommend some form of chemo for stage 3 colon cancer

patients. In Puerto Rico, for example, three - quarters of all stage 3 colon cancer patients got chemo after surger y. Similar numbers are found elsewhere.

Oncologists generally recommend three to six months of a chemo regimen called FOLFOX . The name is derived from the first letters of its three ingredients: FOLinic acid (also known as leucovorin or LV ); Fluorouracil (5-FU); and OXaliplatin (Eloxatin®).

France’s largest drug company, Sanofi, long-held exclusive patents on the drug oxaliplatin, the “OX” in FOLFOX . We shall have more to say about this “French Connection” later.

HINT: Sanofi used to be named Sanofi-Synthélabo or, after a merger, Sanofi-Aventis.

The other key ingredient in FOLFOX is the drug 5-fluorouracil , commonly abbreviated 5-FU (or 5FU). Almost from the start, 5-FU was given along with a helper drug , leucovorin (a .k.a . folinic acid). This seemed to make it work better. The combination of 5-fluorouracil and leucovorin is abbreviated as 5-FU/LV.

5-FU is an old ‘war horse’ of oncology. It was developed and patented in 1957, but is still widely used in the treatment of colon (as well as other types of ) cancer. As two U.S. cancer experts wrote in 2013:

“5-fluorouracil (5-FU) had the fıeld to itself for almost four decades. The fact [is] that no other drug demonstrated meaning ful activity in colorectal cancer during that time….”

HINT: A note about quotations. In this guide we frequently cite sources. We have however taken two liberties with these quotations. First, we sometimes add bold or italic highlights to emphasize keywords and phrases. Second , we sometimes slightly alter or abridge a quotation to make it more readable for a

lay audience. We have tried in ever y case not to change the original intentions of the authors.

SIDE EFFECTS OF FOLFOX

It is important to know the side effects of FOLFOX . We suggest using the Drugs.com website to understand these. They do a ver y complete job of explaining the side effects of almost any drug , as well as its interactions. Here are some of the more common ones associated with 5-FU:

● Heartburn

● Diarrhea

● Sores in mouth and on lips

● Loss of appetite

● Nausea and vomiting

● Skin rash and itching

● Weakness

For about 15 years, 5-FU was the mainstay of treating stage 3 colon cancer after surger y. Then, in 2004, a blockbuster drug came charging into the colon cancer field. This was the well-named “OX . ” Since then, OX has dominated the treatment of stage 3 colon cancer. For years it was sold under Sanofi’s brand name, Eloxatin®. Now it is a generic drug that is marketed under many different names. As the “platin” in the name hints, oxaliplatin is a form of the precious metal , platinum. Two decades ago it was much less known than its more familiar cousins, cisplatin and carboplatin. But all that started to change in 2004. In 2018 alone there were almost a thousand research articles on OX , and it shows no signs of diminishing .

When stage 3 colon cancer patients discuss their treatment options with a medical oncologist, odds are that they are going to be talking about these drugs, 5-FU/LV and OX , in one or another combination. The favored combo is FOLFOX .

This mixture of 5-FU/LV and OX is believed to be more effective than either drug alone. But it is also more toxic. In particular, as you can see at Drugs.com, OX causes damage to the blood and ner vous systems in nine out of ten patients who receive it. According to the U.S. Food and Drug Administration (FDA), the incidence of grade 3 (serious) or grade 4 (severe or life -threatening ) adverse reactions with FOLFOX was 70% versus 31% with just 5-FU/LV.

Your oncologist will probably say that these side effects will go away in time. They usually do. But sometimes, there is long-term or even permanent damage that they rarely tell you.

There are many possible side effects of FOLFOX . We have already listed some of the side effects of 5-FU/LV. But OX itself opens Pandora’s box worth of negatives.

You sometimes hear it said that critics of Big Pharma describe uncommon side effects in order to exaggerate the toxicity of drugs. We won’t do that. We will only list what Drugs.com calls the “more common” side effects of oxaliplatin. Here they are:

● Abnormal tongue sensation

● Black, tarr y stools

● Bleeding gums

● Blistering , peeling , redness, or swelling of the palms of the hands or bottoms of the feet

● Blood in the urine or stools

● Burning , prickling , itching , or tingling of the skin

● Chest pain

● Chills

● Cough

● Decreased feeling , or pain in the hands, feet, around the mouth, or throat

● Decreased urination

● Difficulty performing daily activities such as writing , buttoning , swallowing , or walking

● Difficulty with articulating words

● Difficulty with breathing

● Difficulty with moving

● Difficulty with swallowing

● Dizziness

● Dr y mouth

● Eye pain

● Fainting

● Fever

● Increase in heart rate

● Jaw spasm

● Lightheadedness

● Muscle pain or stiffness

● Numbness, pain, tingling , or unusual sensations in the palms of the hands or bottoms of the feet [peripheral neuropathy]

● Pain in the chest, groin, or legs, especially the calves

● Pain in the joints

● Painful or difficult urination

● Pale skin

● Pinpoint red spots on the skin

● Rapid breathing

● Sensation of pins and needles

● Sore throat

● Sores, ulcers, or white spots on the lips or in the mouth

● Stabbing pain

● Sunken eyes

● Swelling

● Swelling or inflammation of the mouth

● Swollen glands

● Thirst

● Troubled breathing with exertion

● Unusual tiredness or weakness

● Vision changes

● Wrinkled skin

To repeat, those are the “more common” side effects. And this hardly covers what could happen when one mixes this toxic drug with those two other drugs, 5-FU and leucovorin (abbreviated 5-FU/LV ), as is commonly done.

FOUR MAIN WEBSITES

Let us now look at how the four medical websites under discussion deal with the overall question of chemo for stage 3 cancer. This will enable us to compare them for their quality and timeliness.

NCCN GUIDELINES FOR PROFESSIONALS

A basic source of treatment recommendations is the National Comprehensive Cancer Network (NCCN). Its guidelines were created by top U.S. cancer centers, starting over 20 years ago. Before NCCN, almost ever y U.S. hospital went its own way in terms of treatment. If you didn’t like what they were offering , you could go across town and probably get a different recommendation. But nowadays you are likely to be given pretty much the same basic choices wherever you go.

The NCCN has thus succeeded in its stated goal of “harmonizing ” cancer treatment across the entire U.S. In fact, its ambition is global . As they themselves put it:

“Clinicians around the world use NCCN Guidelines® as a standard for clinical decision-making . ”

Each section of NCCN is written by recognized experts and their guidelines are classed into four categories. These are based upon the strength of the recommendation and the degree of agreement of their reviewers. There are 33 experts who contributed to NCCN’s colon report. Ever y one of them is an

American academic physician, usually from a government- designated Comprehensive Cancer Center. Their resumes are impressive, but their point of view is strictly that of orthodox American oncology.

Limitations of Using NCCN

For non-medical readers there are limitations to the Professional Level of NCCN:

1. The language is ver y dr y and may be difficult for laypeople to interpret.

2. There are many chemo regimens for most conditions. Choosing among these options can be confusing .

3. NCCN recommendations come with a set of algorithms. These are flow charts to locate the proper treatment. The average layperson may be unfamiliar with this type of diagram.

Complicated is the best word for NCCN. Getting to the key info is like assembling a dresser from IKEA! But if you want to see what top cancer experts from the U.S. recommend for your cancer, here are the ten steps that you must follow:

1. From all the different pulldown menus, choose “NCCN Guidelines.”

2. Then choose “NCCN Guidelines for Treatment By Site.”

3. For this test case, choose Colon Cancer.

4. Click again on Colon Cancer.

5. Choose the second of ten possibilities, which again reads “NCCN Guidelines.”

6. Either click on the box that says “Continue” or scroll down the page.

7. On page 3 of this e -book, you will find a Table of Contents.

8. Click on the section named “Principles of Adjuvant Treatment COL- G.”

9. Here you will see bulleted items that summarize NCCN’s choices for the best stage 3 colon cancer treatments.

10. To see the exact doses, scroll down one more time to “Chemotherapy Regimens and References.”

NCCN GUIDELINES FOR PATIENTS

Alternatively, you could use the NCCN guidelines for patients. The navigation here is only slightly less complicated than at the Professional site, but the language is simpler.

1. From the home page, choose the tab stating “NCCN Guidelines.”

2. Choose the sixth item, which is “NCCN Guidelines for Patients®”

3. Then choose Colon Cancer. This will download an 88-page electronic book about this disease for patients.

4. Find the scroll bar at the bottom and adjust the type size.

5. Choose Part 4: “ Treatment Guide: Non-metastatic cancer.”

6. Scroll down to the section on “Stage II or III” (2 or 3) colon cancer.

7. Locate the section on Treatment After Surger y (Hint: it is on page 43). This explains the difference between low- and high-risk cases.

8. To find the actual treatment choices, you must go to “Guide 9.”

9. But to find Guide 9 you must go backward one page.

10. Finally, scroll to the bottom of the page.

This is a thoroughly orthodox site, and so, not surprisingly, chemo is recommended for all stage 3 patients. These choices are divided into those

for low-risk and for high-risk categories. ( The differences are explained there.) There are four recommendations for each of these. These are further divided into “preferred” or ordinar y recommendations. This is really the heart of the NCCN:

For low-risk patients, then, NCCN’s choices are as follows:

1. 3 months of CAPOX (preferred)

2. 3 to 6 months of FOLFOX (preferred)

3. 6 months of capecitabine ( Xeloda®)

4. 6 months of 5-FU

For high-risk patients:

1. 3 to 6 months of CAPOX (preferred)

2. 6 months of FOLFOX (preferred)

3. 6 months of capecitabine ( Xeloda®)

4. 6 months of 5-FU

HINT: CAP OX is a combination of the oral prodrug CAPecitabine ( Xeloda®) and OXaliplatin . You may also hear it called XELOX.

So now you have ver y important information to discuss with your oncologist. For instance, let ’s say that she is recommending 6 months of the toxic regimen, FOLFOX . You can say, “But, doctor, NCCN says that 6 months of Xeloda® alone is an acceptable alternative.” Believe me, your doctor will be ver y impressed that you have found and studied the NCCN recommendations!

This is crucial info. Each infusion of FOLFOX is not only more toxic and more expensive but ver y time - consuming . A 2010 study showed that patients

spent an average of two to three hours receiving an infusion. Add to that the time spent traveling to and from the clinic, along with any waiting time, and you can see that it often takes the better part of a day to get each FOLFOX treatment. And this is assuming the drug doesn’t leak from the needle into the surrounding tissue, in a process called “extravasation,” which can take up to 14 days to heal.

The alternative is to take a few peach- colored tablets of Xeloda® at home.

There is some debate over which is more toxic, 5-FU/LV or Xeloda . Most writings on the topic would indicate that Xeloda® is less toxic than its parent drug , 5-FU. It is a “prodrug , ” which only turns into 5-FU after it reaches the liver.

As one clinical trial put it (edited slightly):

“Xeloda® demonstrated a safety profile superior to that of 5-FU/LV, with a significantly lower incidence of diarrhea , mouth sores, nausea , hair loss, and grade 3 or 4 blood system damage, leading to significantly fewer fevers and infections and fewer hospitalizations.”

HINT: The NCI ranks treatment side effects according to a uniform grading system . Grade 1 is mild; Grade 2 is moderate; Grade 3 is severe; Grade 4 is life - threatening or disabling, and Grade 5 is a fatal “adverse event ” related to the drug or combination .

With Xeloda® you have no trips to be treated in the doctor ’s office. No pumps. No infusions of 5-FU. No leucovorin. No PICC line. No extravasation. And, especially, no OX .

However, a medical oncologist of my acquaintance has commented as follows:

“I have never seen a patient NOT get a debilitating hand-foot reaction to it. I think infusional 5-FU is much LESS toxic than capecitabine albeit the inconvenience of being hooked up for 48 hours…as well as the cost.”

So I think it would be a good idea to seek out the opinion of your oncologists on this point, as they may have personal experience with both drugs that they are willing to share with you.

There are also various complementar y treatments that may help reduce the side effects of both of these treatments. One of these is cannabis. But that is too large a discussion to get into here.

The Patient side of NCCN does not tell you the basis for making its particular recommendations. We shall get to that shortly. These Patient Side pages also do not prepare you for the serious, or even devastating , side effects of these regimens. This includes the regimens FOLFOX and CAPOX .

If you access the Professional level of NCCN, as we do, you get some insights that you can’t get from the Patient side. It reveals some of the limitations of the studies on which those Patient Recommendations are based:

1. FOLFOX has NOT been proven to give more benefit than 5-FU to people who are in their 70s (other studies say 70 or older). This is ver y important because the average age for being diagnosed with colon cancer is precisely 70.

2. NCCN affirms that the oral drug Xeloda® alone is as effective as 5-FU/LV, whether the latter is given by injection, infusion, or via a pump. This is an extremely important finding . As stated, Xeloda® is usually less toxic than 5-FU/LV.

3. If you are dealing with stage 2 instead of stage 3 colon cancer you may not need chemo at all . For stage 2, taken as a whole, there is no benefit to any form of post-surgical chemo. In fact, in one influential trial , stage

2 patients who received FOLFOX had a small decrease in sur vival compared to those who simply got 5-FU/LV or Xeloda®. ( This was statistically non-significant.) Chemo is generally recommended only for those stage 2 patients who are considered at high risk.

It is noteworthy that recently NCCN embraced a 3-month regimen of chemo as equal to 6 months for many patients. This means that some people can get 3 months of CAPOX instead of the once -standard 6-months of FOLFOX . The goal is to reduce the amount of ner ve damage (and other toxicity) seen with 6 months of OX .

Overall , NCCN is ver y helpful . But you need the patience to work through the complicated interface. Take the time and tr y to navigate through the Professional Level statements. If not, tr y the Patients’ level .

You will be rewarded with a detailed and generally reliable discussion of your disease and its orthodox treatment options. NCCN is nothing less than the superstructure of American oncology. It is a great resource for stimulating a discussion with your oncologist (who probably uses the same source of information). And access to all of NCCN is free and readily available through any computer or hand-held device.

PDQ

The U.S. government pioneered the first free website to inform doctors and patients about the best treatment for any kind of cancer. This is the PDQ, which officially stands for “Physicians’ Data Quer y, ” It was also obviously a pun on the acronym for “pretty damn quick.” The idea was to deliver up -to - date information for doctors with the help of personal computers.

When we began writing The Moss Report 25 years ago, PDQ was the go -to online source for information about cancer treatment. But for reasons unknown, the NCI has let this information ser vice slip. Nowadays, PDQ is

“pretty damn slow ” at presenting new info to doctors or the public. It gives a good account of how colon cancer treatment progressed over the years. But when it comes to the details of current treatments, it has fallen far behind the times.

And yet they have the ner ve to state:

“ The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available.”

They even claim this particular section was updated in November 2018. But that can’t be true. There are a mere 27 journal articles cited in this whole section. None of them dates from after 2010. There is one from 2009 and none again until you get to 2005.

The same pattern exists in the treatment of other kinds of cancer. PDQ is thus suffering from serious neglect. Yet no administration in the past 20 years, Republican or Democratic, has to our knowledge called NCI officials to account for this fiasco. One angr y word from the President would probably fix this situation “pretty damn quick.”

That said, one can still extract some useful info from this poorly maintained site. Let us, therefore, look at how PDQ describes the best chemo treatment for colon cancer. We will focus on the question of overall sur vival (OS). This is the statistical odds of being alive for a specified time after treatment.

PDQ agrees with NCCN on a crucial point. According to PDQ:

“For patients with stage 3 colon cancer in whom treatment with 5-FU is planned , Xeloda® is an equivalent alternative.”

The bigger question is whether a stage 3 colon patient should also take OX in combination with some form of 5-FU. ( Xeloda® is in fact an oral prodrug form of 5-FU.) Does OX really improve one’s chances of sur vival?

Here is what PDQ says:

“Oxaliplatin [OX] has significant activity when combined with [5-FU] in patients with metastatic colorectal cancer.”

Significant Activity?

Sometimes medical writers use words like “significant activity ” when they lack evidence that a treatment actually extends sur vival . After all , they could have said, “OX is proven to extend overall sur vival when combined with 5-FU/LV.” But they didn’t. Instead, they talked rather vaguely about “activity,” which could mean a number of different things.

Like most writers in the field, PDQ puts a lot of emphasis on the MOSAIC study. MOSAIC refers to the “Multicenter International Study of Oxaliplatin/ Fluorouracil/ Leucovorin in the Adjuvant Treatment of Colon Cancer.”

PDQ explains:

“In the MOSAIC study, the toxic effects and efficacy of FOLFOX were compared with the same 5-FU regimen without oxaliplatin administered for 6 months.” space below

They further state:

“Based on results from the MOSAIC trial , adjuvant FOLFOX demonstrated prolonged overall sur vival for patients with stage 3 colon cancer compared with patients receiving 5-FU without oxaliplatin . ”

This is technically true. There was “prolonged overall sur vival” in the stage 3 group that got FOLFOX versus those that got just 5-FU/LV. But many readers will be surprised to learn that, at the time of publication (2004), this “prolonged sur vival” amounted to just a 2.5% increase over 5-FU/LV alone. (After 10 years, this number had risen to 4.6%, but PDQ seems unaware of

this.) Meanwhile, the side effects from adding six months of OX increased dramatically.

PDQ on Side Effects of Treatment

Let ’s also look at how PDQ handled the question of FOLFOX’s side effects. This is a major issue for most patients confronting this treatment. We’ll focus on just two common side effects of FOLFOX , These are “peripheral sensor y neuropathy ” or ner ve damage; and neutropenia , which is a decrease in a type of white blood cells. The original paper reported (edited slightly):

Serious ner ve damage “during treatment was reported in 12.5% in the FOLFOX group versus 0.2% of the patients in the 5-FU group.

Among 976 patients who were assessed for ner ve damage 18 months after the end of treatment, 24.1% had symptoms of any grade, with 0.7% reporting grade 3 symptoms. At 48 months, grade 1, 2, and 3 ner ve damage were obser ved in 11.9%, 2.8%, and 0.7% of the patients examined , respectively.”

Odds of Having Ner ve Damage

To repeat, the odds of developing serious to severe ner ve damage in the FOLFOX group was 12.5% versus 0.2% in the 5-FU group. That ’s a large difference. Plus, most lay people have no idea what “peripheral sensor y neuropathy (PSN)” really means. But here is how the Mayo Clinic website describes it:

“A result of damage to your peripheral ner ves, often causes weakness, numbness and pain , usually in your hands and feet. It can also affect other areas of your body….People with [peripheral neuropathy] generally describe the pain as stabbing, burning or tingling . ”

Grade 3, or serious, ner ve damage might include the following:

“Disabling sensor y loss, severe PSN pain , obstipation [severe or complete constipation], severe weakness, bladder dysfunction . ”

The title of a book from the American Academy of Neurology speaks volumes:

“Peripheral Neuropathy: When the Numbness, Weakness, and Pain Won’t Stop.”

One patient, writing at the Drugs.com website, had this to say (edited slightly):

“After four years, severe and chronic peripheral neuropathy persists, particularly in the feet and would seem to be permanent. I was completely unaware before, and while having, treatment that this condition could happen after ceasing my course of treatment. Unfortunately on some days walking becomes extremely painful and is a huge struggle.”

But in the Abstract of the paper, the MOSAIC authors downplay the prevalence of ner ve damage with OX . Here’s what they state:

“Among patients receiving oxaliplatin , the frequency of grade 3 peripheral sensor y neuropathy was 1.3% 12 months after treatment and 0.7% at 48 months.”

This minimizes the problem. But you would need to read the whole paper itself to get a true picture of toxicity.

HINT: Always tr y to read full papers, not just Abstracts. Increasingly, full papers are available free of charge through PubMed or Open Access websites.

For instance, the MOSAIC authors could have highlighted the fact that 92% of FOLFOX recipients developed ner ve damage during the course of treatment. Or that two years after completing treatment, over 20% were still

experiencing some degree of numbness, pain and/or tingling . Neuropathy became a long-term condition for 15.4% of FOLFOX recipients. But instead, the MOSAIC authors highlighted the lowest available figure (0.7%), thereby giving the impression that side effects were minimal . And here is how PDQ summarizes the same data (edited slightly):

“Patients treated with FOLFOX experienced more frequent toxic effects consisting mainly of neutropenia and reversible peripheral neuropathy.”

Really? To be clear, for most people there was a decrease in the frequency and severity of ner ve damage over time. But, four years on, it was not reversed for about one in seven patients. This is shown graphically in the paper ’s Figure 5. But this fact is flatly denied at the PDQ site.

The authors of a 2018 meta-analysis in the New England Journal of Medicine, in their discussion of this topic, concluded:

“Neurotoxicity often peaks several months after the last oxaliplatin exposure….Such toxic effects can be severe and persist long beyond the actual treatment, which potentially affects patients’ activities of daily living for the rest of their lives.”

To be clear, the word “reversible” does not appear in the MOSAIC paper. Why then do the PDQ authors blatantly understate the toxicity of this drug regimen?

3. THE DEVITA TEXTBOOK

Next, we come to what was for years the “go -to” source of cancer treatment. This is the famous textbook edited by Vincent T. DeVita , Jr., MD (former director of the National Cancer Institute), and two prominent colleagues, Theodore S. Lawrence, MD, and Steven A . Rosenberg , MD. It has hundreds of other contributing writers and editors.

HINT: You may also see this referred to by its original title, DeVita , Hellman and Rosenberg ’s Cancer: Principles & Practice of Oncolog y.

“DeVita” is fully searchable from any computer or hand-held device. We purchased the printed book, but this comes with access to the e -book as well . In addition, they are promising to update the entire work on a quarterly basis. This is extremely helpful if you do not want to miss emerging findings in oncology.

Sometimes the opinions of the DeVita authors clarif y the choices offered by the NCCN and other sources. DeVita remains an outstanding resource that ever y serious student of cancer needs to know about.

HINT: The list price of the book is $369, but at this writing , Wolters Kluwer is offering a seasonal 25% discount. This price at Amazon may be as low as $250. The DeVita textbook is frequently available at any well- equipped librar y or through interlibrar y loan . It is tempting to pick up old editions of the book for far less money online. But always stick with the latest edition . Out- of- date medical information can be dangerous to your health .

We routinely check the online edition of this book when we are writing and updating The Moss Report. One of the key features is that it is updated quarterly.

Let ’s now look at the online updated section on stage 3 colon cancer.

First, being a writer for DeVita is prestigious, and they get many top experts to write their chapters. The chapters are by-and-large well-written but occasionally hard to interpret. The authors clearly expect the reader to have a higher education. You should have your NCI Dictionar y of Cancer Terms at the ready.

What does the 11th edition of “DeVita” have to say about chemo for stage 3 colon cancer?

“It is clear that patients with [lymph] node -positive colon cancer should receive postoperative chemotherapy. At the ver y least, a 5-FU–based regimen would appear to be appropriate, and approximately 6 months of therapy would be supported by the majority of trials.”

Recommending a “5-FU based regimen” is like recommending vanilla ice cream! For 40 years, almost ever y type of chemo for colon cancer has including some form of 5-FU, including 5-FU/LV, FOLFOX , FLOX , XELOX , CAPOX or oral Xeloda®. So if your doctor is recommending a regimen without either 5-FU or Xeloda® that is ver y unusual .

But the DeVita authors seem skeptical of current thinking by saying that six months of therapy are necessar y. Clinical trials published in 2017 and 2018 showed that in many cases three months of therapy were as good as six months, with fewer side effects. This is clearly stated in the NCCN Guidelines discussed above.

As to FOLFOX , here is what the DeVita authors write in the 2019 edition:

“At this time, the data for incorporation of oxaliplatin into the routine adjuvant treatment of colon cancer appears compelling, and the FOLFOX schedule is now the most widely used adjuvant therapy.”

True enough. But do we sense some hesitation here? The word “appears” is odd. It is as if the authors were not quite convinced that FOLFOX is the right treatment, but tell us that it is “ the most widely used” treatment. We don’t need to know what ’s most popular. We need to know what ’s factually proven to be safe and effective. So perhaps they share some of our doubts about the MOSAIC trial?

They conclude (slightly edited):

“At the time of this writing, FOLFOX or XELOX are the regimens of choice in treatment of all patients with stage 3 colon cancer in the absence of specific contraindications.”

Then they throw this cur ve ball:

“ The long- term morbidity [state of being damaged or diseased] of oxaliplatin treatment has become more appreciated … ”

Actually, the side effects of oxaliplatin have been known for a long time. PubMed has over 3,500 articles that reference this topic! Back in 1986, after the first small clinical trial , French researchers obser ved:

“Gastrointestinal toxicity, nausea and vomiting, similar to those with cisplatin , occurred in all patients….”

So the DeVita statement seemed disingenuous since ever yone knows that the side effect profile of OX is profound. The 11th edition (2019) of DeVita’s book has clarified some of what they are only alluding to here.

HINT: It is best for references to be included because they give the reader a chance to double - check an expert ’s assertions with PubMed . They are important for successful DIY research .

How up -to - date is the online edition of the DeVita textbook? It leaves PDQ in the dust in its grasp of current research. In the past, the timeliness of its online updating was sometimes disappointing . For example, in 2018, there were only two extended updates to this section of the book. They seemed a bit slow to cover the emerging transition from a six-month to a three -month course of treatment.

But the 11th edition of 2019 has proven to be much better in this regard. There is a detailed discussion of the strengths and weaknesses of the IDEA study. The authors’ comment:

“ The IDEA trial does not provide straightforward , simple answers to the optimal duration of therapy for patients with stage III colon cancer. Taken at its simplest, the study missed its prespecified primar y endpoint, and we could therefore conclude that 3 months of therapy is non-inferior to 6 months. However, we must keep in mind the considerably increased toxicity, especially neurotoxicity, that is associated with longer duration of oxaliplatin therapy.”

It is encouraging that the 11th edition of DeVita seems thoroughly up -to - date. Plus it provides insights into subtle aspects of the IDEA study that could definitely influence one’s treatment decision. At The Moss Report we will continue to use this outstanding book as one of our “go -to” sources. We encourage all “DIY researchers” to do the same.

UPTODATE.COM

Now we come to our favorite site for medical information here at The Moss Report: UpToDate.com.

HINT: This is also the most expensive. A full-year subscription normally costs $495 per year. However, patients can buy a 7- day subscription for $20 and a 30- day subscription for $53. You may also be able to get free online access to UpToDate if your librar y has a subscription. This is particularly so if you live near a medical librar y that is open to the public. Lists of these are available on the internet. UpToDate is a critical modern reference source for half a million physicians worldwide.

Unlike some other sites we have considered, UpToDate fully lives up to its name. Its information is current and you can be confident that you are getting the latest findings. The chapter on stage 3 colon cancer was actually updated within days of the time we were writing this DIY Guide.

The expert authors and editors are clearly identified, so you know who is “ talking . ” In this case, they are an Associate Professor of Medicine at Har vard Medical School and another at the University of North Carolina at Chapel Hill . They did an excellent job. Their writing is clear and to the point.

The UpToDate article begins by stating ver y clearly that surger y is the only curative treatment for stage 3 colon cancer. Its outcome will be “most closely related to the extent of disease at presentation.” Then the rationale for post-surgical chemo is also clearly presented:

“For patients who have undergone potentially curative resection , disease recurrence is thought to arise from clinically occult micrometastases that are present at the time of surger y. The goal of postoperative (adjuvant) therapy is to eradicate these micrometastases, thereby increasing the cure rate.”

Well put. The UpToDate authors also explain why and how they are convinced that the benefit of adjuvant chemo is proven by an increase in disease -free sur vival (DFS) at two or three years. Many of us will still need convincing on this point because the histor y of cancer is filled with instances in which DFS in the end did not improve OS. But they make a careful , fact-based argument for accepting DFS as proof of effectiveness.

Next, they deal with the question of when one needs to begin chemo. None of the other four sites raises this point. This is where the UpToDate authors’ clinical focus pays off:

“Adjuvant colon cancer trials typically mandate initiation of chemotherapy within six to eight weeks of resection , and this has become an accepted approach . ”

However, there’s the rub. In the real world, the time between surger y and the start of chemo is often more than eight weeks. Patients may have trouble recovering from bowel surger y or have other reasons for holding off. It is

important to realize that patients who waited more than seven weeks were excluded from the MOSAIC trial . So we do not know whether such patients would be benefited— or possibly harmed—by intense chemo. In other words, to quote UpToDate:

“ Whether a delay in the administration of adjuvant therapy compromises outcomes is controversial . There are no randomized trials addressing this issue in patients with resected colon cancer.”

UpToDate is clearly not a site that aims to promote the use of chemo, or any other treatment, for that matter. That ’s quite refreshing .

After a good discussion of the evidence, pro and con, they conclude:

“ We still suggest that adjuvant chemotherapy be started within eight weeks of surger y, if at all possible.”

But how is this to be done if the patient is still suffering from the ill effects of surger y (such as an infection)? Nor do they address the many socio - economic factors (such as all the consequences of poverty) that often lead to a delay.

All the same, this discussion offers clear-headed practical knowledge, which is hard to come by in the other resources. It comes from authors who have vast experience as clinicians as well as scholars.

How do the UpToDate authors handle the use of FOLFOX in stage 3? One might expect the same old “party line.” But on the whole, you will be happily surprised.

They first remind the reader that six months of OX-based chemo has been the standard of care for adjuvant treatment of stage 3 colon cancer. But they then suggest that “a shorter duration of therapy might be advantageous if equally effective.”

They also admit to “ the cumulative and dose -limiting toxicity ” of OX , especially ner ve damage. (Contrast that with PDQ’s claim that this is “reversible.”)

This is the only one of the four sources that clearly states that, for many people, six months of OX might be excessive. They also give the latest 10-year updated figures from the MOSAIC trial (something lacking from the other sites):

● Ten-year overall sur vival in the 5-FU/LV group was 67.1% versus 71.7% in the FOLFOX arm. In other words, there was a 4.6% greater chance of being alive at ten years in the study population as a whole if they take OX . ( This was a 2.1% improvement over the six-year figure of 2.5%.)

● In stage 2, overall sur vival with 5-FU/LV was 79.5% versus 78.4 for FOLFOX . That ’s right: overall sur vival was 1.1% less in the FOLFOX versus the 5-FU/LV group! But this difference was not statistically significant and may have been due to chance.

● In stage 3, overall sur vival (OS) with 5-FU/LV was 59% versus 67.1%, which was an 8.1% difference. This is considerable if the subset analysis reflects reality. But OX comes at a high price in terms of toxicity. And such findings may not apply to a great number of people, such as those who are frail or elderly, or who do not begin FOLFOX within seven weeks of their colon surger y.

THE FLOX TRIAL (NSABP C-07)

But the most revealing thing at UpToDate is not its discussion of the MOSAIC trial , useful as that is. It was showing that MOSAIC was not the final word on the effectiveness of OX in this situation. UpToDate also discusses another trial , which compared a ‘close cousin’ of the FOLFOX regimen versus 5-FU/LV alone.

This trial was technically named NSABP C-07. In this guide, we will call it the FLOX trial . It originated with the well-known American clinical trial group, the National Surgical Adjuvant Breast, and Bowel Project (NSABP) of Pittsburgh, PA .

The FLOX trial compared a weekly bolus dose (an injection given over a short period of time) of 5-FU/LV with those same two drugs plus OX . In other words, FLOX contained the same three drugs as FOLFOX but given in a different schedule.

The FLOX paper states the following (slightly edited):

“Overall , the addition of OX to 5-FU/LV has not been proven to extend overall sur vival in this trial , but the disease -free sur vival effect remained strong .

“Unplanned subset analyses suggest a significant overall sur vival effect of oxaliplatin in patients younger than age 70.

“ With eight years of follow-up, five -year disease -free sur vival significantly favored FLOX (69% versus 64%) but the difference in overall sur vival was not statistically significant ( five -year overall sur vival 80% versus 78%).”

HINT: In medicine, the word “significant ” has a different meaning than in ordinar y speech . To quote the NCI Dictionar y, “A difference is said to be significant when it is greater than what might be expected to happen by chance alone.”

This is ver y clearly presented. But it raises some serious questions about the effectiveness of OX . In particular, it needs underlining that in this trial , OX did not significantly improve overall sur vival . The lack of statistical significance means that the meager 2% sur vival advantage could have been due to chance.

For the FLOX study, the authors enrolled 2,409 stage 2 and 3 colon cancer patients. In the total trial population, adding OX failed to cause a significant rise in overall sur vival (OS). However, unlike in MOSAIC, it did not show an overall sur vival advantage in stage 3 patients. Yes, there was some improvement in disease -free sur vival (DFS). But as you can see, this did not translate into a significant rise in overall sur vival (OS). Here is the most relevant finding:

“ The effect of oxaliplatin on OS did not differ by stage of the disease.

Overall , the addition of oxaliplatin to [5-FU/LV] has not been proven to extend OS in this trial . ”

That ’s an astonishing statement. It flies in the face of 15 years of the promotion of FOLFOX by the medical mainstream and the almost unanimous opinion of all oncologists. But the FLOX summation is not merely someone’s contrar y opinion. It is a hard fact established by a large American clinical trial .

Also, by stating that “no positive effect was evident in patients older than 70,” they thereby exclude a lot of patients from receiving OX . About half the colon cancer patients are over 70. Yet many writers on this topic do not warn people over 70 of this.

Claims for the effectiveness of OX that were made on the basis of MOSAIC are seriously undercut by the FLOX trial . It certainly reopens the question of whether OX is worth its extreme toxicity.

UpToDate, to their great credit, is the only one of the four sources to fully discuss the FLOX trial . PDQ does not mention it. The 10th edition of the DeVita textbook makes only a passing reference to it. But UpToDate gives it the attention it deser ves.

And they go further. They point out that “ toxicity was prominent in both groups.” This included hospitalization for diarrhea or dehydration and grade 3

or 4 vomiting in 13% of the FLOX group. We are all familiar with vomiting , of course, but the usual case of “ the heaves” hardly encompasses what is meant by “grade 3 or 4 vomiting . ” An oncology nurse practitioner described grade 4 vomiting this way:

“Grade 4 is patients having so much [vomiting] that they have to be on parenteral nutrition [intravenous feeding] or other support to keep them from disintegrating in front of your eyes.”

UpToDate informs readers that “ five deaths in the FLOX group were directly attributed to chemotherapy-induced enteropathy, versus one in the control group.” Enteropathy is a disease or inflammation of the intestines. But since the only difference between FLOX and 5-FU/LV was the addition of OX , it is hard to escape the conclusion that it was OX alone, or its interaction with other drugs, that caused this extreme reaction.

This horrendous side effect (in the oncology nurse’s words, “patients disintegrating in front of your eyes”) is truly shocking . Remember that these patients had no signs of remaining cancer. They were only taking this harsh treatment in order to prevent the possibility of their disease recurring . Yet they died months or years ahead of time because of the side effects of those drugs, and not of the cancer they were tr ying to prevent. This is the kind of situation that makes many people cr y, “ There’s got to be a better way!”

At least UpToDate reveals these startling facts to their subscribers so that they can make up their own minds about the value of this treatment.

There is much more useful information at UpToDate. But the main point is that UpToDate lives up to its name. It is thorough, well- organized, and reasonably easy to read. It never insults your intelligence the way some other medical websites do. The major drawback is the price. But you can consult it for free at some medical libraries that offer public access. Considering the

wealth of information that it presents, it is a necessity for those who need a clear and thorough presentation of current medical thinking .

3-MONTH REGIMENS

It is encouraging to see any indication that oncology is adopting a more humane stance. One sign of this is that many oncologists are now proposing a three -month regimen of chemo instead of the previous six months. This could reduce the ner ve damage from the 5-FU and OX combo, without significantly diminishing its effectiveness.

Six months of FOLFOX became the world standard for hundreds of thousands of patients when it was approved by FDA and other regulator y agencies in 2004. Soon afterward, there were complaints about the serious and sometimes long-lasting side effects of FOLFOX . However, it took almost a dozen years for these complaints to change medical practice.

A turning point came in 2012 when the FLOX trial group showed that “numbness and tingling of the hands and feet remained significantly elevated for oxaliplatin-treated patients.”

The key word was “remained.” The following year saw the launch of the International Duration Evaluation of Adjuvant Chemotherapy, or IDEA . IDEA was designed to see if a 3-month course of OX- containing chemo was as good as standard 6 months. IDEA was not itself a clinical trial , but an analysis of 6 ongoing clinical trials with over 12,800 patients. Their main endpoint was disease -free sur vival (DFS) at 3 years. The results were announced by Axel Grothey, MD, of the Mayo Clinic at the Plenar y Session of the 2017 ASCO Annual Meeting (Abstract LBA1). These were then published in a medical journal in 2018. (Dr. Grothey is now at Sarah Cannon, Nashville, TN.)

HINT: We shall leave aside, for now, the ability of disease -free sur vival or DFS to stand in for the more meaning ful overall sur vival , or OS (overall

sur vival). In this section , we shall use the word “sur vival” in quotes to denote disease -free sur vival (DFS).

The differences between the “sur vival” of patients receiving 3 months or 6 months of OX (whether included in FOLFOX , FLOX , XELOX or CAPOX) were ver y small . The ASCO Post concluded (edited slightly):

“ Three months of chemotherapy was nearly as effective as six months in patients with relatively lower recurrence risk and caused fewer side effects, particularly ner ve damage.”

We will paraphrase ASCO’s three key takeaway points from the important IDEA study:

● For all patients combined, the rate of “sur vival” (DFS) at 3 years was just 0.9% lower with 3 months of chemotherapy than with 6 months of chemotherapy.

● The type of chemo selected affected the difference in 3-year “sur vival” between the 3-month versus the 6-month treatment duration. There was a 1.1% decrease with CAPOX and a 2.4% decrease with FOLFOX .

● Meanwhile, the rate of grade 2 or greater ner ve damage was consistently higher for people who received 6 months versus 3 months of chemotherapy. There was a 30% decrease for FOLFOX and a 31% decrease for CAPOX .

According to Dr. Grothey:

“ These findings could apply to about 400,000 colon cancer patients worldwide ever y year. For 60% of these patients, who have a lower risk for cancer recurrence, 3 months of chemotherapy will likely become the new standard of care.”

In a detailed analysis of the IDEA study, an ASCO Post author made an excellent point about the devastating effect that ner ve damage could have on different individuals:

“Concert pianists and violinists, guitar virtuosi , and microvascular surgeons would likely require much greater benefits to risk career- ending toxicities to increase 5-year overall sur vival by percentages in the low single digits.”

For now, the main question is, How well did the four information sources cover this development? We are writing this DIY Guide a year and a half after Dr. Grothie presented the results of the IDEA study at the ASCO meeting . So if these cancer information sources were current, they should definitely have a discussion of it.

1. NCCN has the correct information, although there isn’t a detailed analysis of the results.

2. PDQ writes about the 2009 MOSAIC trial , but about little since then. Their page on this topic is 10 years out of date. It does not mention other OX combinations such as CAPOX . Any doctor relying on PDQ might give 6 months of OX , when 3 months would suffice. So a hapless patient might suffer a 30% greater chance of ner ve damage caused by 3 extra months of FOLFOX , which they didn’t need.

3. The DeVita textbook authors have a complete and intelligent analysis of the IDEA study. They cite the IDEA paper that was published in 2018 in the New England Journal of Medicine.

4. But kudos go to the UpToDate authors and editors. They clearly explain that 3 months of CAPOX is as good as 6 months, with less toxicity. They state that there was a slight benefit to 6 months with the FOLFOX regimen, especially in high-risk cases. Of course, as the ASCO Post discussion shows, the difference in “sur vival” with FOLFOX was only

2.4%. But grade 2 or greater ner ve damage in those receiving 6 months of FOLFOX was 47.7% versus 16.6% of those who got just 3 months of the same treatment. This is an absolute reduction of over 30%. Similar numbers were seen in regard to the CAPOX regimen.

GOOGLING FOR ANSWERS

At any point during your DIY research, you may feel the need to consult primar y sources. For example, you might need to check on some statements being made at the PDQ site. To do this, open a new tab and formulate a question for the Google search engine. You could for example ask Google the following: “How many weeks between surger y and chemo for colon cancer? ” It will return the following statement, which is extracted from a Korean paper:

“It is usually accepted that adjuvant chemo should begin within 8 weeks after surger y. ”

This is helpful since we know that patients in the MOSAIC trial were started on FOLFOX at seven weeks, or one week earlier than was usually expected. But this didn’t answer the key question: How many weeks on average do patients in the real world waited before beginning their chemo treatment?

This would compare the carefully selected MOSAIC patients with “real world” patients in various countries, including the U.S., under ordinar y circumstances.

So you could rephrase the question this way:

“What percentage of patients can’t start chemo 8 weeks after surger y? ”

This leads to two promising citations, which can then be looked up in PubMed. These studies showed that the majority of real-world patients

actually waited longer than the recommended time of six to eight weeks. This probably decreased the effectiveness of the treatment.

We learn that if you are older, sickly, poor, African-American, have health insurance problems, or live 100 miles or more from the hospital in question, your chances of being treated within that 6-week to 8-week window diminishes. This reinforces doubts about how relevant the MOSAIC findings are for the general patient population.

There is indeed evidence that, with colon cancer, you need to start chemo fairly soon after surger y in order to achieve the desired outcome. Any more than an eight-week delay before starting chemo results in a decrease in sur vival . By how much? The overall sur vival (OS) rate in those who started chemo within 8 weeks was 90% versus 81% in those who delayed past week eight.

But, in fact, many real-world patients are not able or willing to start chemo within six to eight weeks of their surger y. In eastern Canada , for instance, most stage 3 colon cancer patients did not get chemo until at least 8.5 weeks after surger y. In fact, many patients did not start chemo until 10 or more weeks of delay.

HINT: The percentage of patients who did not get chemo until more than eight weeks after surger y was 76.4% in those who had complications of surger y and 81.4% in those who delayed further treatment for non-medical reasons, such as the consequences of poverty..

In a 2017 study at M.D. Anderson Cancer Center in Houston, one in five colon cancer patients delayed taking chemo for more than eight weeks after surger y. They experienced a 9% decrease in overall sur vival (90% vs. 81%).

Unplanned readmission to the hospital , prolonged postoperative stays, or the development of other medical conditions, all caused a delay.

But surgical complications are common ever ywhere. A Dutch study appearing in 2019 shows that many patients suffered serious complications after colon cancer surger y:

“Complications occurred within 30 days after surger y in the laparoscopic group in 26.1% of patients and in 32.1% of patients in the open [surger y] group.”

HINT: A laparoscope is “a thin , tube -like instrument with a light and a lens for viewing . ” It is sometimes used for less invasive surger y.

All of these people (around 30% of the patient population) would have been barred from participating in the MOSAIC trial by this fact alone. For all such patients, the benefits of FOLFOX are speculative. MOSAIC ’s results cannot be applied to them or to tens of thousands of others around the world.

For anyone who doesn’t start FOLFOX within 7 weeks of surger y, as for people in their 70s, MOSAIC is thus of unknown value. We do not know if it would be better or worse for them than simply taking Xeloda® tablets or doing nothing .

Having many inclusion and exclusion criteria in a trial can make a treatment seem better than it will actually perform in the real world. So, as we interpret the results of clinical trials, such as MOSAIC, we have to remember that patients in such trials are sometimes “cherr y-picked” to yield better outcomes for the drug under study.

It is also disquieting to realize that some of the doctors involved in the MOSAIC study were recipients of monetar y rewards from the ver y company that had the most to gain from a positive outcome of the trial .

Subset or Subgroup Analyses

There is another important question to consider when evaluating clinical trial results. This is from a paragraph from PDQ about the MOSAIC trial (edited slightly}:

“Follow-up at 6 years demonstrated that the overall sur vival (OS) for all patients entered into the study was not significantly different. On subset analysis, the 6-year overall sur vival in patients with stage 3 colon cancer in the patients receiving FOLFOX was 72.9% versus 68.7% in the patients receiving 5-FU.”

This represented a 4.2% improvement at 6 years. This was the finding , more than anything , that led to the FDA’s approval of FOLFOX in 2004.

But there’s a hitch. The NCI Dictionar y of Cancer Terms defines a subset analysis as follows:

“In a clinical study, the evaluation of results for some but not all of the patients who participated . The selected patients have one or more characteristics in common , such as the same stage of disease or the same hormone receptor status.”

PDQ quotes the results of these subset analyses without comment. But let ’s dig deeper. You may remember that the MOSAIC trial included patients with two different stages of colon cancer, stages 2 and 3.

FOLFOX yielded no benefit for the total patient population. It was only when the authors subdivided the original group into two subsets that they found that 4.2% benefit from FOLFOX for stage 3 patients.

PDQ glosses over this and concludes by stating:

“FOLFOX has become the reference standard for the next generation of clinical trials for patients with stage 3 colon cancer.”

But “subset analyses” (also called subgroup analyses) such as this are considered by most statisticians to be fraught with problems.

Here’s why. Clinical trials are supposed to define their treatment group in advance and then make an analysis of all the patients whom they intended to treat. ( This is called an “intent-to -treat ” or “intention-to -treat ” analysis). This analysis must ensure the following:

“All participants who are randomized are included in the statistical analysis and analyzed according to the group [to which] they were originally assigned . ”

There is a potential for abuse when researchers perform subset analyses. If a trial is inconclusive or achieves results worse than what researchers had hoped, there is a temptation to subdivide the data . Do this often enough, and you might eventually find a group for whom it appears beneficial:

“ When subgroup analyses are not correctly analyzed and reported , incorrect conclusions may be drawn , and inappropriate treatments provided . ”

An intention-to -treat analysis guards against this. According to an article from the University of California at Ir vine:

“ This method allows the investigator (or consumer of the medical literature) to draw accurate (unbiased) conclusions regarding the effectiveness of an inter vention” (Mc Coy 2017).

Mc Coy CE. Understanding the Intention- to - treat Principle in Randomized Controlled Trials. West J Emerg Med . 2017 Oct;18(6):1075-1078. doi: 10.5811/westjem .2017.8.35985. Epub 2017 Sep 18. PMID: 29085540; PMCID: PMC5654877.

In the case of the MOSAIC trial , the authors first combined stages 2 and 3 in a single cohort. But when FOLFOX did not improve the outcome in the overall group, they re -analyzed the data by stages. Stage 2 still showed no benefit. But, according to this re -analysis, after six years there was a sur vival benefit of 4.2% for stage 3 patients.

It was on this basis that six months of FOLFOX became the standard for the treatment of stage 3 colon cancer all over the world. It is also how OX became a more than $1 billion a year “blockbuster drug ” for the French drug giant, Sanofi.

But subdividing data after the fact is not to the liking of most statisticians. According to the Concise Encyclopedia of Biostatistics:

“Popularly termed ‘ torturing the data until it confesses,’ data are sometimes over- analyzed , particularly in the form of post-hoc analysis.”

There is widespread recognition of this problem. Here are the opinions of some other statisticians on this topic:

1. “ There are some clinical investigators who ransack their data to find a subset of patients in which their new therapy looks effective. They report the findings in apparent ignorance of the problems and their statistically significant finding looks good to the mass of statistically unsophisticated readers….The phrase ‘subset analysis’ itself acquires a connotation of deception and sophistr y. ”

2. “While the subset analysis provides valuable insights to subject population , it can be easily mismanaged or misinterpreted . ”

3. Performing subset analyses “can result in misinterpretation of the data . Such analyses must, therefore, be performed and evaluated with caution . ”

As a rule, one tries not to base treatment recommendations on subset analyses. Yet PDQ seems unaware of the problem. They ignore the frequent warnings of statisticians and recommend an aggressive treatment based on this subset analysis.

LIMITATIONS OF CLINICAL TRIALS

In this era of “evidence -based medicine,” treatment recommendations are usually based on the outcome of randomized controlled trials (RCTs). But it is important to understand why the findings of clinical trials may not be automatically applied to the general population of patients.

Clinical trials like MOSAIC are, by design, artificial treatment situations. They are called “controlled” trials for a reason. Doctors who carr y out these human experiments generally impose strict “inclusion” and “exclusion” criteria for who can participate. Not ever yone is welcomed into them. One basically have to be in reasonably good health in order to gain admittance. In fact, for a variety of reasons, only 5% of cancer patients participate in trials. As a result, patients included in clinical trials may not actually represent the patients found in the general public.

A 2007 sur vey in the Journal of the American Medical Association (JAMA) found that many patients were commonly excluded from trials:

“ Women , children , the elderly, and those with common medical conditions are frequently excluded from RCTs….Such exclusions may impair the generalizability of RCT results.”

This is a profoundly important point. Many cancer patients do have “common medical conditions,” other than cancer. But clinical trials often limit participation to a carefully selected group. Their results may be impressive for that group, but may not predict the outcome for the general population. In

the “real world,” patients may have a worse response, more toxicity, or may even need to stop the treatment prematurely.

Yet once a treatment like FOLFOX becomes approved on the basis of a clinical trial , as happened with MOSAIC, it is common to give it to a wide swath of patients, even those who themselves would have been excluded from the original trial .

We know that the MOSAIC authors laid down stringent requirements for participation in the trial . These included:

● No visible ( gross) or microscopic evidence of remaining disease

● Treatment had to be started seven weeks or less after surger y.

● Patients had to be younger than 75 years of age.

● Patients could walk on their own and be capable of all self- care with a Karnofsky performance status of at least 60.

● They could not have had any prior chemotherapy, immunotherapy, or radiotherapy.

● They had to have adequate blood counts and liver and kidney function.

● Their carcinoembr yonic antigen (CEA) level had to be less than 10 ng per milliliter.

Needless to say, all of these conditions do not apply to many “real life” patients. People with multiple chronic conditions represent more than one - quarter of all Americans. According to a report from the A ARP Public Policy Institute:

“As people get older, the prevalence of chronic conditions increases. They use more prescription drugs and medical devices, and experience more complications and adverse drug events than younger, healthier

patients. By the time they reach Medicare eligibility, one - quarter of the population has five or more chronic conditions and is responsible for more than two - thirds of Medicare spending . ”

For all those people, the results of the MOSAIC trial may be an unreliable guide to postoperative treatment. Yet many of them get FOLFOX anyway.

“Underrepresentation of older, sicker adults in clinical trials makes it difficult to understand the full impact of medical inter ventions and may lead to inappropriate use of inter ventions in these populations.”

POTENTIAL CONFLICTS OF INTEREST

Clinical trials are usually designed and paid for by big drug companies that have an enormous stake in the outcome. Successful drugs, like OX , can earn $1 billion or more per year during the duration of their patents (which are 20-year legal monopolies).

So, needless to say, drug companies have a lot riding on the outcome of clinical trials. Not surprisingly, they also have many techniques to increase the chance of a positive outcome.

One of the disturbing things they do is financially reward some of the lead doctors who participate in these trials. This sort of undue influence has been described many times, including by leaders of the medical field. For example, Marcia Angell , MD, a former top medical editor, wrote in 2009:

“Conflicts of interest and biases exist in virtually ever y field of medicine, particularly those that rely heavily on drugs or devices. It is simply no longer possible to believe much of the clinical research that is published or to rely on the judgment of trusted physicians or authoritative medical guidelines. I take no pleasure in this conclusion , which I reached slowly and reluctantly over my two decades as an editor of The New England Journal of Medicine.”

We know from disclosure statements required by some journals, that at least five of the MOSAIC authors were taking payments from Sanofi, France’s largest pharmaceutical company, until its patents ran out, Sanofi owned and marketed OX under the brand name Eloxatin®. In 2004, worldwide sales of Eloxatin® were $1.5 billion. Seven years later the drug was still going strong at $1.2 billion per year. So we can surmise that in less than a decade Sanofi had about $10 billion in sales of Eloxatin®.

Since the only approved use of OX was, and is, to treat colorectal cancer, most of those sales were based on FOLFOX . And regulator y agencies’ approval of FOLFOX as an adjuvant treatment mainly rested on the results and interpretation of the MOSAIC trial .

Having well-known and respected oncologists as public spokespersons for a drug is a priceless asset for a company. In fact, the enthusiastic support of the main researchers is a critical part of a company ’s marketing strategy. Such doctors not only appear in the mass media but work as paid participants in a company ’s “Speaker ’s Bureau ” , tout the benefits of the drug to fellow doctors, who, as a result, then prescribe it to their patients.

It ’s clear how this benefits the company. But how does it benefit the oncologist?

That is not typically revealed in disclosure statements. But the world recently got a peek behind the curtain surrounding this topic. This came from a New York Times exposé of none other than the president of Memorial Sloan-Kettering Cancer Center:

“Dr. [Craig B.] Thompson received $300,000 in compensation from [the American drug company] Merck in 2017, according to company financial filings. He was paid $70,000 in cash from Charles River [another drug company] in 2017, plus $215,050 in stock . ” This was in addition to “his 2016 salar y from MSKCC of $6.7 million . ”

Cancer can be a good business for prominent academic physicians! Aimer y de Gramont, MD, the head of oncology at a big Paris hospital , was the doctor who first proposed adding OX to 5-FU/LV for colon cancer. He coined the catchy term FOLFOX and was senior author and chief spokesperson for the MOSAIC trial .

But his own disclosure statements show that he was simultaneously a consultant, on the Speaker ’s Bureau, and received unspecified “honoraria” from Sanofi, as well as from Merck and Roche.

“Prof. de Gramont was not exceptional in this regard . Far from it. Five other oncologists who participated in the MOSAIC trial report deriving financial benefits from Sanofi , including the paper ’s first author, Dr. Thierr y André. But Prof. de Gramont was the most prominent interpreter of the MOSAIC trial . ”

You might ask, “How can a person objectively evaluate a treatment while taking money from the patent holders of that treatment? ” We must leave it to others to figure that one out.

This per vasive influence of Big Pharma is one of the reasons that we must examine all claims of a drug ’s effectiveness ver y carefully. One should be leer y of statements from supposedly “objective” scientists who are simultaneously in the pay of the companies whose drugs they are evaluating . The harshest judgment on such “complicity with big business” was rendered by Jerome P. Kassirer, MD, another former editor-in- chief of the New England Journal of Medicine. Such doctors, he said, are simply “On the Take.”

PROBLEMS WITH CLINICAL TRIALS

In this era of evidence -based medicine, drug approval ultimately rests on the outcome of randomized clinical trials (RCTs). In 1989, the U.S. Preventive

Ser vices Task Force (USPSTF ) put forth RCTs as the only type of high- quality

“Level 1” evidence for any proposed medical treatment. This is the be -all and end-all for Big Pharma and the FDA .

But randomized clinical trials can obscure as much as they reveal .

Patients who are enrolled in a clinical trial are a special breed. Only 5% of cancer patients enter such trials. They must pass stringent “inclusion” and “exclusion criteria” to gain admittance. The end result is that patients who get into clinical trials are more likely to withstand the side effects or respond to treatment than those who are excluded. Clinical trials tend to concentrate on younger, healthier, and more economically secure patients.

This focus sometimes yields positive results, which then form the basis of crucial regulator y approval . But one is left wondering what would happen if the same drug was tested in more typical real-world patients? Older people? Poorer people? Sicker people?

A QUESTION OF AGE

In the MOSAIC trials, patients who did not meet all of the trial’s preconditions were excluded from the trial . This included being younger than 75 years of age. Let us then focus on this question of age. The average age for receiving a diagnosis of colon cancer is 70 (68 for men and 72 for women).

Colon cancer is, to a large degree, a disease of one’s later years. As one journal article put it:

“ The greatest burden from colorectal cancer falls on the elderly, with nearly 70% of cases diagnosed in those older than age 65 and 40% diagnosed in those over 75 years of age. As a result, approximately 75% of colorectal cancer deaths occur in people older than 65 years of age.”

Since people who are up in years are often excluded from clinical trials, such as MOSAIC, no conclusions can be drawn about the effectiveness of chemo in

this age group. For older people, the safety and effectiveness of FOLFOX or CAPOX are basically unknown.

We do know, however, that “severe white blood cell toxicity “is increased in older age groups treated with chemotherapy.”

One concern is the interaction of chemo with other drugs in the patient ’s system. Seniors are after all the biggest consumers of prescription drugs:

“More than one - third of prescription drugs used in the U.S. are taken by elderly patients; the ambulator y elderly fill between 9-13 prescriptions a year (including new prescriptions and refills); the average elderly patient is taking more than five prescription medications; the average nursing home patient is taking seven medications.”

But when doctors prescribe FOLFOX to such people, they are adding two or three dangerous drugs on top of the five to seven that a typical elderly patient is already taking . This is not to mention their possible intake of vitamins, food supplements, alcohol , tobacco, cannabis, etc.

According to Drugs.com, there are 625 other drugs that can interact with oxaliplatin! This includes 94 major drug interactions. The other main drug in FOLFOX , 5-FU, interacts with a “mere” 274 other drugs, including 55 major and 197 moderate interactions. Among the latter is its interaction with, you guessed it, oxaliplatin (OX). In fact, the list of interactions between these two alone is long and painful to read. Here is an excerpt from drugs.com:

“Using fluorouracil together with oxaliplatin or other chemotherapy drugs may increase the risk of side effects, especially those that affect the bone marrow or gastrointestinal tract. You may experience a greater number or more severe side effects such as nausea; vomiting ; diarrhea; loss of appetite; mouth sores; abdominal pain; delayed wound healing ; and impaired bone marrow function resulting in low numbers of different types of blood cells. You may

also be more likely to develop anemia , bleeding problems, or infections due to low blood cell counts. You should seek medical attention if you develop paleness, fatigue, dizziness, fainting, unusual bruising or bleeding, fever, chills, diarrhea , sore throat, muscle aches, shortness of breath , blood in phlegm , weight loss, red or inflamed skin , body sores, and pain or burning during urination . ”

This is part of “real life” conditions, where doctors have to treat patients as they find them, with all their typical health problems, frailties, and limitations. But this is a far cr y from the artificial world of most randomized clinical trials.

SUMMATION

There are many sources of medical information on the internet, some of them freely available to patients. But we have focused on four that, over the years, we have used most at The Moss Report. Nowadays, the two that we use constantly are the DeVita textbook and UpToDate.com. NCCN is reliable but difficult to use. PDQ is now mainly of historical interest and as a result, can sometimes be misleading .

We urge ever y reader to approach all medical websites in a spirit of what we have called “ friendly skepticism.” Either excessive credence or excessive mistrust can lead one astray. You need to combine goodwill towards cancer clinicians and researchers with a willingness to question the most basic assumptions in the field.

In this guide, we have demonstrated how to research a single situation, the post- operative chemotherapy of stage 3 colon cancer. You should now be able to take these same tools and carr y out a similar analysis of whatever stage and type of cancer you are dealing with.

ON A PERSONAL NOTE

Some readers have wondered what I myself would do if I ever developed stage 3 colon cancer. My first goal would be to find the best and safest hospital available, as close to home as possible. This question can be researched with such fine resources as the U.S. News and World Report ’s ranking of Best Hospitals for Cancer.

It is standard to have surger y to remove the affected part of the colon. The exact type of surger y would depend on discussions with the surgeon. It is generally best to be conser vative and agree to the least invasive, radical , or destructive methods that are consistent with a good outcome. It may take some searching to find this. It might be worthwhile to travel some distance from home, if necessar y, in order to receive superior treatment.

Not ever yone can withstand the rigors of bowel surger y. A British study raised the question of whether surger y is even feasible in some patients:

“Although surgeons are naturally focused on surgical outcomes, non- operative outcomes are equally as important for patients. Elderly, frail patients benefit less from surger y for bowel cancer and have higher risks than younger cohorts, and this needs to be carefully discussed when jointly making the decision whether or not to operate.”

In such cases, one needs to go straight to some systemic therapy, such as chemo or immunotherapy.

As to post- operative chemo, one can insist on the least toxic regimen. That might be a course of Xeloda®. NCCN allows for this type of treatment in its guidelines. We know that Xeloda® is generally as effective but somewhat less toxic than 5-FU/LV. [Some oncologists dispute this, however.]

One could also explore the field of “low- dose metronomic chemotherapy.”

This consists of “the frequent administration of comparatively low doses of

cytotoxic agents, with no extended breaks.” This sort of treatment is little practiced in the U.S., but is better known elsewhere. There are presently over 350 references to low- dose metronomic chemo in PubMed. A pan-European expert meeting concluded:

“A full consensus was reached concerning the acknowledgment that [low- dose metronomic chemotherapy] is not simply a different way of administering chemotherapy but a truly new treatment option . ”

There is exciting work using Xeloda® along these lines at the Technion, Israel’s Institute of Technology, Sunnybrook Health Sciences Center, Toronto, and elsewhere. So one could possibly use a low daily dose of Xeloda® in just that way and avoid the toxicity of higher amounts.

Personally (and I am speaking only for myself ) I would avoid oxaliplatin (OX). There are reasons to be skeptical of the claims made for it based on the MOSAIC Trial . The results of the FLOX Trial seem to more closely reflect the reality for most patients. Plus, it is hard to forget that some of the leaders of the MOSAIC trial were taking “honoraria” from the manufacturer, Sanofi, while simultaneously boosting its results.

Another possibility would be to skip chemo entirely and go straight to an immunotherapy treatment facility abroad. But that is a stor y for another day.

I would certainly combine the use of any chemotherapy with a comprehensive regimen of natural and nutritional agents. First and foremost would be the addition of curcumin, the most active ingredient in the turmeric rhizome/root. Why curcumin? A rare clinical trial in Leicester, U.K . contrasted the standard regimen FOLFOX with an addition of two grams per day of curcumin (a combination the authors called CUFOX). The mere addition of four 500 mg capsules of curcumin, taken at breakfast and dinner, more than doubled the overall sur vival of the patients by more than 100%. There was a “hazard ratio” (HR) of 0.57 for progression-free sur vival (PFS) in the CUFOX

group, which translates into a 47% reduction. There was an even greater impact on overall sur vival (OS). The hazard ratio for death was 0.34, or a 66% reduction. The median overall sur vival was 200 days with FOLFOX versus 502 days for CUFOX , which means a net gain on average of 302 days. The full paper is available free online at PubMed:

(Howells LM, Iwuji COO, Ir ving GRB, et al . Curcumin Combined with FOLFOX Chemotherapy Is Safe and Tolerable in Patients with Metastatic Colorectal Cancer in a Randomized Phase IIa Trial . J Nutr. 2019 Jul 1;149(7):1133-1139. doi: 10.1093/jn/nxz029. PMID: 31132111; PMCID: PMC6602900)

Although this was not tested, I would combine this use of adjuvant curcumin with at least four other agents, in other words, Cord Naujokat and Dwight McKee’s “Big Five.” I believe this would give the greatest chance of retarding the growth of colorectal cancer by directly targeting the cancer stem cells (CSCs).

(Naujokat C, McKee DL . The “Big Five” Phytochemicals Targeting Cancer Stem Cells: Curcumin , EGCG, Sulforaphane, Resveratrol and Genistein . Curr Med Chem . 2021;28(22):4321-4342. doi: 10.2174/0929867327666200228110738. PMID: 32107991)

Turn static files into dynamic content formats.

Create a flipbook
Issuu converts static files into: digital portfolios, online yearbooks, online catalogs, digital photo albums and more. Sign up and create your flipbook.