June 3, 2015 — Rituximab’s Latest Dance Partner

Some encouraging news from the world of lymphoma research:

“Polatuzumab plus rituximab in relapsed/refractory follicular lymphoma showed high overall response rates at two doses of polatuzumab, with a higher complete response rate at 2.4 mg/kg, data presented at the 2015 American Society of Clinical Oncology (ASCO) annual meeting have shown....

Researchers enrolled 45 patients with relapsed/refractory follicular lymphoma and assigned them to receive polatuzumab at 2.4 mg/kg or 1.8 mg/kg with rituximab 375 mg/m2 every 21 days until disease progression or unacceptable toxicity.

Results showed that overall response rates were 76% (19/25) and 75% (15/20) in the 2.4 mg/kg and 1.8 mg/kg groups, respectively.”

Rituximab — which I received, in conjunction with the CHOP chemotherapy cocktail in 2006 — continues to be the gold standard in treating non-Hodgkin lymphoma. For refractory (recurring) disease, the doctors are continually trying new combinations of rituximab with other drugs. This combination — for indolent disease — is the latest variation.

Keep at it, researchers!

January 8, 2015 - What You Can't See in the Tide Pool

A poignant personal reflection on life and death, today, from Anne Lamott's book, Traveling Mercies:

We were, in fact, going to learn later that afternoon that my father had a brain tumor on the word section of his brain, a metastasized melanoma, something no one had ever survived at that time. In just a week or so, doctors were going to take out as much of the tumor as they could, but they weren't going to be able to get it all; its tentacles reached deep inside his brain. He was going to come home from the hospital to his girlfriend's house looking like Dr. Frankenstein had had a go at him. He was going to have the most aggressive forms of radiation and chemotherapy available, be part of a clinical trial that wouldn't work for him; he was going to have one good year in between these treatments where he would be able to work off and on, and walk with us every day; he was going to live to see John graduate from Berkeley; he was going to live to see my younger brother graduate from high school; he was going to live to see me sell a novel about our family to a fancy New York publisher; he was going to live to read a draft of it while his brain was still functioning.

But then the cancer was going to start to eat away at his mind, and he was slowly going to end up like a huge friendly toddler. He was going to have to bear knowing for a while that his mind was going; he was going to have to bear letting his kids and girlfriend dress him, clean him, feed him; he was going to end up living at the one-room cabin with me and Steve, his girlfriend and oldest friends around, playing Pete Seeger on the stereo, and Billie Holliday, Joan Baez, and Mozart, the Modern Jazz Quartet. He was going to end up in a coma a month before he died, the cabin turned into a hospice room and us the stricken nurses. My father's handsome fair face was going to have tumors on it— tumors on the skin that today was flushed with health. The cancer was going to spread like a chain of stores, and he was going to need morphine and catheters and lemon swabs and fleecy bedding. Maybe he would hear the music we played on the stereo in the cabin, maybe he would be aware of us watching him through the night, but what we did not know that day on the lava rock was that he was going to die two years from this August morning—this morning when the three of us were walking about peering into tide pools, with our dog Muldoon bumping into our legs, the late-summer diffusion of light making everything in the pools seem larger: the sea anemones, the bloom of algae, the tiny crabs.

November 17, 2014 — Bye, Bye Bexxar

There are many ways our market-driven healthcare-funding system in the United States is just plain crazy, but one of the most damaging is the way it tends to suppress certain vital and effective medications. This has evidently just happened to Bexxar, which is no longer available. Along with its competitor Zevalin, Bexxar is a radioimmunotherapy agent.

Radioimmunotherapy is an ingenious bonding of a monoclonal antibody drug — Rituxan (rituximab) — with tiny radioactive particles. It delivers a one-two punch: the Rituxan chemically seeks out the cancer cells and the radioactive particle destroys them.

Radioimmunotherapy has proven to be very effective, and has the added advantage of doing its job in just one dose, with minimal side effects.

What’s not to like?

The people who really don’t like it are oncologists. And why? Because not many of them have the proper qualifications to administer it. As a hybrid of nuclear medicine and oncology, radioimmunotherapy requires doctors either to be dual-certified in both disciplines or to be part of a large clinic or group where both specialties are represented (a rare thing, in this case).

Many oncologists profit on two levels: both their professional fees and the fees they charge for running a chemotherapy suite. If their chemo suite doesn’t offer nuclear medicine as well, they lose a big chunk of change by referring a patient out.

An oncologist who refers a patient for radioimmunotherapy loses tens of thousands of dollars in billable fees. That’s a powerful financial incentive to stick with traditional chemo — even though that treatment takes longer (many months of infusions as compared to a single injection) and often has arduous side-effects.

This is not a problem for a large, multi-specialty clinic, but the typical oncology practice — which includes a group of oncologists only — can’t handle it. As Dr. Bruce Cheson of Georgetown University puts it, “patients had to be referred from one doctor to somebody somewhere else, which meant not only losing control of the patient, but also losing income from the patient.”

In many cases, radioimmunotherapy agents cost less — not as a single dose, but when averaged out over the total time required for treatment.

“There is actually no other drug out there with a track record like this,” writes Dr. Mark Kaminski of the University of Michigan, who helped devlop Bexxar. “Approximately 30% of patients can achieve long-term remission with Bexxar lasting over a decade. That's the biggest disappointment with this drug, now that it's gone, for patients with this disease — it was an easy treatment, it took only one week to finish, and if there were any side effects, they were all reversible. I've been giving Zevalin lately because I don't have Bexxar to work with, but I don't have as much confidence that it will be a solution for patients as much as Bexxar would have been.”

If we had a single-payer healthcare system (like Medicare), and if doctors practiced in multi-specialty clinics like the Mayo Clinic or the Cleveland Clinic — where they receive a salary rather than billing patients by the hour — then doctors wouldn’t stand to lose by recommending radioimmunotherapy. More patients would benefit.

Why do we expect physicians to be both medical practitioners and entrepreneurs? Sometimes those two functions are in conflict with one another, and this is a prime example.

Too often in our healthcare system, profits come first and patients second.

August 9, 2014 - A Promising Discovery

"I have seen the future of cancer treatment, and its name is... Silvestrol?”

I’m not qualified to make such a claim, of course, but maybe some knowledgeable researchers who are would go so far as to say such a thing. There’s a bit of hyperbole in that statement, but it’s an eye-catching way to point out a new discovery that could be a really significant development in the long term, for blood-cancer patients.

According to an article the Leukemia and Lymphoma Society has been sending around, Silvestrol is a compound derived from “a plant called Aglaia foveolata, which is native to Indonesia, Brunei, and Malaysia.”

Rather than attacking a certain well-known cancer-causing gene, this stuff prevents it from being produced at all.

The tree is an endangered species, whose habitat is threatened by development.

An older article, chronicling the substance’s discovery, is here.

This reminds me of a movie that came out a while back, Medicine Man (1992), starring Sean Connery and Lorraine Bracco. Two courageous botanists fight off developers, whose bulldozers are about to ravage a section of Amazonian rain forest where a promising cancer drug has just been discovered. They bicker then fall in love, of course. (Hey, it's Hollywood, what do you expect?)

There’s more on the website of Memorial Sloan-Kettering (which is where Silvestrol’s treatment potential is being investigated)). “Blocking the production of key cancer genes is a completely new way of treating cancer,” says Dr. Hans-Guido Wendel, a Memorial Sloan-Kettering cancer biologist. “That is exciting, and it also means we have a lot to learn about it.”

I will likely be years before any patients can be treated with this new drug, but its discovery is certainly something to celebrate.

April 27, 2013 — A Pretty Good Pipeline

With all the ecological concern these days, pipelines don’t have an especially good name. Surely they’re a mixed blessing. They deliver all sort of things we can use, but they can pose terrible risks to the environment.

Here’s one pipeline whose value everyone can agree on. It’s the pharmaceutical research pipeline. I saw an article today directing me to an online brochure detailing just how many new medicines are in the pipeline for blood cancers.

From the brochure: “Pharmaceutical research companies are developing 241 medicines for blood cancers — leukemia, lymphoma and myeloma. This report lists medicines in human clinical trials or under review by the U.S. Food and Drug Administration (FDA). The medicines in development include 98 for lymphoma, including Hodgkin and non-Hodgkin lymphoma, which affect nearly 80,000 Americans each year.”

The brochure includes this chart (click to enlarge), which details the complex process each of these drugs must go through before they’re ready for prime time:

Most don’t make it: not even to clinical trials. Out of many thousands of promising compounds, only about 250 get real scrutiny as possible clinical-trial material. Of these, only five get tried out on real, live patients.

Four out of these five drugs turn out to be ineffective, or deliver side effects that are just too intolerable. That leaves just one chemical compound out of 5,000 to 10,000 that makes it through clinical trials into production.

This, of course, is why new drugs cost so much. The companies have to set aside enough money to pay for all those failed experiments. Patents allow the companies exclusive manufacturing rights for only a limited number of years. Once that time period has elapsed, the generic manufacturers start selling their own inexpensive knock-offs (and, of course, their research and development cost are negligible). The original manufacturers drop their prices to compete, and begin looking to whatever new formula is next coming down the pipeline.

It’s a complicated system. I wouldn’t want to be the accountant who figures out the financial risk and tells the company executives how much they need to charge. But I am glad to know this process is taking place — and that the outlook for new blood-cancer medications is so promising.

With every new drug that emerges from the pipeline, my prospects for living out a normal lifespan, even with my lymphoma — now quiescent, thank God — look better and better.

June 25, 2012 – Tweaking the Cocktail

If ever there were a good time to be a lymphoma patient (not that I think there ever is), it’s now.  Every annual meeting of ASCO (the American Society of Clinical Oncologists) seems to offer news of some new variation on treatment protocols that promises a heightened survival rate.

The latest one for follicular lymphoma – as I learn today from an e-mail bulletin sent around by the Leukemia and Lymphoma Society – is a new combination of Rituxan (the monoclonal antibody drug I received along with my CHOP chemotherapy) and an old drug that’s been around for a while, Revlimid:

“John Leonard, M.D., of Weill Medical College of Cornell University presented promising results for a Phase III trial of a new Rituxan combination to treat patients with follicular lymphoma (FL). Dr. Leonard reported that using Revlimid plus Rituxan very much increased overall response rates for relapsed FL patients (73% in this trial vs. 50% for Rituxan only in previous trials). A Phase II trial of this combination for newly diagnosed FL patients is already underway.”

Revlimid, its manufacturers admit on their website, is an “analogue” of Thalidomide – one of the scariest names out there in the field of pharmacology. OK, let’s be real: Revlimid is Thalidomide, but with the drug’s notorious history I can understand why they’d rename it.  I still remember, as a kid, paging through an issue of LIFE magazine with its chilling, black-and-white photos of the children born with horrible birth defects as a result of that drug.  From 1957 to 1961, Thalidomide was commonly given to expectant mothers to prevent morning sickness.  No one knew that many of the children born to these unfortunate mothers would have no arms – other than small, vestigial appendages that could in no way substitute for the real thing. Very sad.  (Not to mention, a gold mine for the trial lawyers.)

As a cancer drug, Revlimid is evidently effective: and, as long as the patient isn’t an expectant mother, it’s supposed to be safe (or, at least, as safe as most other cancer drugs, all of which have a certain risk to them).  Lots of chemo drugs come with a warning label saying they’re not for expectant mothers, or may cause sterility.  Doctors have raised that sort of warning with me, at various times as I prepared for treatment, but when I tell them Claire and I are not only done having children, but that I’ve had a vasectomy, it lays those concerns to rest pretty quickly.

It’s not cheap, though: Wikipedia.com reports that Revlimid (medical name, Lenalidomide) costs an average of $163,381 per year.  Ouch.

Dr. Leonard’s work is only a Phase I trial, with Phase II now underway, so this drug cocktail is a long way from being ready for prime time.  I’m glad to know someone’s out there, though, with the medical-research equivalent of a cocktail shaker, trying out new drug combinations.  From early indications, chances are that this one may be in production in several years’ time, so it's one more reason to be hopeful, should the day come when I need treatment again.

December 23, 2011– Mademoiselle Zevalin’s Empty Dance Card

Interesting article, here, about the difficulties ibritumomab tiuxetan (Zevalin) has been having, getting accepted as an effective treatment for non-Hodgkin lymphoma.

So, at the Oncologists’ Ball, why is Zevalin – which is actually a pretty hot little number – treated like such a wallflower?  Dr. John Pagel, of the Fred Hutchinson Cancer Research Center and Seattle Cancer Care Alliance, thinks he understands the reason:

“Unfortunately, oncologists still have to refer the patient to a radiation oncologist or nuclear medicine physician for administration of the drug, which can be a barrier for treatment in some cases.”

Gee, d’ya think?

For most oncologists to prescribe Zevalin for their patients, they have to give up the privilege of dispensing treatment themselves.  Since many oncologists – who have invested big bucks in elaborate chemo suites, where they dispense medicines costing tens of thousands of dollars – earn their money not just from the medical wisdom they dole out, but also from the meds, telling a patient “I think Zevalin could help you” means foregoing the income from several months of costly chemo treatments.

Is it any wonder so many oncologists stick to the classic approaches, which just so happen to use the treatment agents they’re licensed to dispense?

Zevalin, along with Bexxar (the other leading drug of this type), is the highly-effective Rituximab bonded with radioactive particles.  The CD-20 targeting agent in Rituximab seeks out and travels to the malignant cells – unleashing Rituximab’s own cancer-fighting properties – but then the radiation zaps ‘em again.  It’s a potent one-two punch.

Sort of reminds me of the sharks with laser beams that were the weapon Dr. Evil lusted after in the silly Austin Powers movies.  Rituximab’s the shark.  Radiation’s the laser beam.  Get it? (Can you hear the screams of a metaphor being stretched beyond all recognition?)

How do you suppose radioimmunotherapy studies of drugs like Zevalin are received at professional conferences, when very few of the members of the professional association are licensed to dispense the drug?  (Doctors who administer radioimmunotherapy have to be double-qualified, both in oncology and in either radiology or nuclear medicine.)  These docs-on-holiday hear reports of the science behind these treatments, and they can’t really argue with it, but it can’t fail to enter their minds that, in order to prescribe these drugs, they’ll have to let some other doctor’s practice collect the revenue.

I’m not charging oncologists with running some kind of cartel or cover-up.  It's just that I'm enough of a Calvinist to point out that they’re only human, and therefore such a thought can’t fail to enter their minds.

Again, it’s the basic structure of our healthcare system that’s the real root of the problem. Force doctors to function as small-business entrepreneurs who are paid according to treatments dispensed rather than according to clinical outcomes, and a proven drug like Zevalin gets pushed to the back burner.

It would be interesting for someone to study which sorts of oncologists are referring patients for radioimmunotherapy more often – those who own their own practices, or those who work for organizations like the Mayo Clinic, where they’re all on salary.

Are there any investigative journalists reading this, looking for a scoop?  Just crunch those numbers. I’ll bet you’ll see a correlation.

October 6, 2011 – Designer Drug Is a Little Closer

Back in October, 2007 and again in June, 2009, I reported on the research success of an idiopathic vaccine treatment for indolent NHL called BiovaxID.  I’ve been following the progress of this research with particular interest ever since, because I was briefly considered for a clinical trial of it when I was first diagnosed.  While that clinical trial proved not to be an option for me (after I was diagnosed with an aggressive from of NHL, besides the indolent form the researchers were targeting), it’s one of the newer treatments that continues to hold promise.  By the time my indolent NHL-dragon awakes from slumber and again rears its ugly head, BiovaxID will likely be one of the arrows in the quiver.


A current financial news article reports that BiovaxID is just about ready for prime time.  Biovest, the company that holds the patent, has just formally petitioned the FDA for regulatory approval.

The wheels of government bureaucracy grind exceeding slow, but this is progress, all the same.

It’s a little odd to read about it in an internet investors’ newsletter called Market Watch.  Articles like this one are meant to help aspiring venture capitalists see what's coming from afar, so they can decide whether  shares of Biovest’s stock are an attractive place to park some of their simoleons.

In the world of Big Pharma, though, that’s the way it works.  It’s not just altruism that keeps those researchers peering into their microscopes and hovering their eyedroppers over petri dishes.  If you can “build a better mousetrap” by curing or pushing back some dread disease, the investment world will beat the proverbial path to your door.  That means some big, fat paychecks for the people in the lab coats, and even fatter ones for those risk-taking financiers who advanced them the money to do what they do best.

BiovaxID is the ultimate designer drug, in that it’s custom-manufactured for each patient.  Starting with some biopsied tissue, the drug company goes back to the lab and cultures a special version of the drug that will be most effective for that person’s body chemistry.

This feature of the treatment stretches the meaning of the word “drug.”  You’ll never be able to amble down to your local pharmacy and pick up a childproof bottle of the stuff.  Each person’s formula is one-of-a-kind.

What BiovaxID will eventually cost, I have no idea. It sure won’t be cheap. It is to ordinary drugs as a Saville Row bespoke tailor is to K-Mart.

Whatever it takes to get the researchers as far down the road as they’ve gone on this one, I’m glad they have.

Another reason for hope!

October 1, 2011 – Drug Shortages: I’m Not Alone

According to a recent item in The Atlantic, I’m not alone in experiencing the effects of a drug shortage (the Thyrogen shortage, that’s currently shoved my radioactive-iodine treatment onto a siding).

The FDA has documented no fewer than 178 drug shortages so far this year. From the article: “The number of drug shortages has been steadily rising every year since 2006, when 56 shortages were reported. It increased to 90 in 2007, 110 in 2008, 157 in 2009, and finally to 178 in 2010, more than tripling in four years.”

There are lots of reasons for these shortages, evidently, including: “manufacturing problems, drug purity issues, and discontinuations of some older, less profitable drugs by drug companies.”

The FDA’s trying to get Big Pharma to agree to a regulation that would require them to give 6 months’ notice before discontinuing a drug, to allow the FDA time to seek new avenues of supply for patients who need it. The pharmaceutical companies are resisting this, complaining that it’s often because of oppressive FDA regulations that they can’t make a profit on their drugs in the first place.

What insufferable arrogance! Who’s the regulator here, and who’s the regulated?

Still no word from Memorial Sloan-Kettering on when they may get some Thyrogen and be able to schedule my treatment. Late August has become late September, and still no word. Now we’re into October.

Considering the extremely lucrative nature of the drug-manufacturing business, and the critical importance of some of these medications for patient health, you’d think these companies could take the small steps necessary to at least let patients know a shortage is coming.

But that would be too ethical, it seems.

September 20, 2011 – Still Waiting for Thyrogen

The other day I looked at the calendar and said, “Hey, wasn’t I supposed to hear back from Dr. Fish’s office in New York about scheduling my radioactive iodine treatment?”  They’d been waiting on news about the availability of Thyrogen, the medication I need to be given just before the treatment.  The estimate at the time was that the drug would be available to them in mid- to late-August.

I sent them an email (that’s something patients can do with Memorial Sloan-Kettering doctors, through a special patient website they’ve got set up – unlike most other doctors’ offices, that are still hopelessly mired in the age of the telephone).  This morning I checked back on the site, and here’s the reply:

“At this time Thyrogen is not available for the treatment. We do expect an update soon. As soon as we receive Thyrogen we will contact you regarding scheduling.”

Doesn’t tell me much, but at least it tells me that the worldwide shortage of the drug is continuing.

Patents are supposed to protect the intellectual-property rights of inventors, I know, and in that respect they’re a very good thing.  Yet, when the invention in question is a drug, and there’s only one company worldwide that’s licensed to manufacture it, I think the company has a special responsibility to be sure the drug remains available.  I wonder, is there any provision in the law for taking a drug patent away from a company that fails in such a massive way, so other companies can step in and make sure the supply continues?

Dr. Fish told me the manufacturing process for Thyrogen takes three months.  It’s been more than three months, now, since the shortage began. Makes me wonder what’s going on with these people.

August 7, 2011 – Drug Shortage

On Friday, I rode the train into Manhattan for a consultation with Dr. Stephanie Fish, my newly-assigned endocrinologist from Memorial Sloan-Kettering.

I found Dr. Fish to be well-informed about my case, and ready with answers to all my questions about my upcoming radioactive-iodine treatment (the routine follow-up to my thyroid surgery recommended by the surgeon, Dr. Boyle).

I did encounter one problem I hadn’t expected. Dr. Fish explained that, as an essential part of my preparation for taking the radioactive-iodine pill, I will be injected with a drug called Thyrogen a few days before. There’s currently a shortage of this drug, due to some manufacturing problems at Genzyme, the company that makes it. It’s simply not available.

Genzyme has been acquired by a larger pharmaceutical company, Sanofi-Aventis. I don’t know if that acquisition has any role in the supply problem. I did learn that there were some quality-control issues with Genzyme’s manufacturing process for Thyrogen, which led the FDA to order a temporary suspension of sales.

This shortage was reported in the New York Times in May, although I missed reading about it.

Genzyme has issued an advisory statement about future availability of the drug.

Dr. Fish explained that Memorial Sloan-Kettering is the single largest user of Thyrogen in the country (and is therefore Genzyme’s best customer), so they expect to be at the head of the line when the medicine is finally handed out. Even so, she doesn’t expect that to be for several weeks at least, and even that is uncertain.

What Thyrogen does, she explained, is to raise the level of TSH, or thyroid stimulating hormone, in the body. For people who still have their thyroids, TSH is what tells the thyroid to ratchet up its production of thyroid hormone. In order for the radioactive iodine to be effective in hunting down and destroying any stray particles of thyroid tissue that may still be present after surgery, the level of TSH must be high.

The old-fashioned way to do this is to have patients simply stop taking their thyroid medication (synthroid or levothyroxine) for a couple of weeks. This makes them feel really lousy, as the body copes with the acute shortage. Thyrogen directly raises the TSH level, without the side effects, so it’s by far the most desirable way to conduct the radioactive-iodine treatment.

This would be well and good, were Thyrogen presently available. But, it’s not. So, patients are faced with an undesirable choice between two options. They can either proceed with the treatment and brave the miserable side-effects, or wait until the drug is available, and risk the consequences of delaying treatment.

In my case, she says, there’s no extreme hurry. The papillary thyroid cancer I have is generally slow-moving, and even though my tall-cell subtype is a bit more aggressive, still there’s nothing to be lost from waiting till sometime in the fall to undergo the treatment.

Even so, this shortage makes me uneasy, and also a bit angry. The pharmaceutical companies are protected by patents, which allow them to make a great deal of money for a period of time after they bring out a new drug. This, they claim, is the only way they can recover their substantial research and development costs. Yet, that also means that, if there's a manufacturing or distribution problem, the patients are out of luck. There's no competitor to fill the gap.

Dr. Fish’s office will call me as soon as they know for sure when they’ll have my Thyrogen injections in stock, so we can get some dates on the calendar.

There’s a lot more to say about the details of the radioactive-iodine treatment, the extensive dietary preparation leading up to it, and the safety procedures that must be followed afterwards, but I’ll save that for a subsequent blog post. The drug-shortage problem must be overcome first.

September 29, 2010 - Watch Those Cancer Cells Get Zapped

Thanks to Betsy de Parry for posting a link on Facebook to an animated slide show about how targeted therapies (like Rituxan, the drug I received) first locate, then take out, cancer cells.

It's on the website of the National Cancer Institute. The presentation is in a lot of different segments. You need to click on the links in the menu to the right to move on to the next one.

It's nice to see those cancer cells getting zapped, even if it's only an animation!

August 27, 2010: Cancer-Fighting's New Cocktail Party

An article in Business Week, "Cocktails Are Next For Cancer-Drug Makers," highlights what its author calls a new development in cancer treatment. Comparing newly-developed cancer drug combinations to the drug cocktails that have been successful in treating HIV/AIDS, the author says:

"For more than a decade, cancer researchers have been crafting drugs to disrupt the precise cellular processes that fuel cancer, creating a $51 billion market in 2009. So far, the survival benefits have been measured in months, not years. That's because cancer, like the virus that causes AIDS, evolves rapidly to evade a single treatment. Rather than mixing and matching approved drugs, researchers are developing new, targeted combinations that work in tandem to block cancer.

'We're looking to see a radical change in terms of stopping the disease in its tracks,' says Tal Zaks, head of global oncology drug development at Sanofi in Paris. 'The return on investment here is not going to be just evolutionary; it has the potential to be revolutionary.'"

I don't get it. What's so new about chemo cocktails? I got R-CHOP (Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisone) five years ago. Isn't that a targeted drug cocktail?

R-CHOP is concocted of three chemo agents and a steroid, linked up with Rituximab, a monoclonal antibody that does the targeting.

How is this different from what the Business Week article is talking about? Can anyone enlighten me?

July 13, 2010 – Bendamustine Rising

Thanks to Betsy DeParry of the Patients- Against-Lymphoma group on Facebook, for posting excerpts from an article about Bendamustine in the treatment of indolent NHL.

Bendamustine (trade names Treanda, Ribomustin) is a chemotherapy agent that’s been around for decades. It was developed in East Germany during the Cold War, which is perhaps why it was slow to catch on in the U.S. and Western Europe. It’s receiving a lot of attention these days as a treatment option for NHL, either in conjunction with Rituxan or on its own.

The full article is found in the issue of the American Journal of Health-System Pharmacy (2010; 67: 713-723). Authors are Anjana Elefante, Pharm.D., B.Sc.Phm., Clinical Pharmacist, Department of Pharmacy; and Myron S. Czuczman, M.D., Chief, Lymphoma/Myeloma Service, Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY.

Here are some excerpts from Betsy’s excerpts:

“Bendamustine is an alkylating agent that has a unique, multifaceted mechanism of action. Compared with other alkylators, bendamustine produces more-extensive and long-lasting DNA damage. Bendamustine also inhibits cell-cycle checkpoints, leading to mitotic catastrophe and apoptosis.”

Sounds pretty dire, eh? Well, the “DNA damage... mitotic catastrophe and apoptosis” is actually referring to cancer cells, so that’s not such a bad thing.

“Bendamustine is approved for the treatment of CLL and for indolent B-cell NHL that has progressed during or within 6 months of treatment with rituximab or a rituximab-based regimen. In Phase II and III trials in patients with indolent NHL and CLL, bendamustine has demonstrated response rates of 67–84% as a single agent and median durations of response of 7–21 months. Additional clinical trials are examining bendamustine as a single agent and in combination therapy for the treatment of hematologic malignancies and solid tumors. Adverse events associated with bendamustine are typically mild to moderate and can usually be managed with supportive care.”

Sounds pretty encouraging.

“NHL is the most common hematologic cancer and the sixth most common cancer in the United States, with an estimated 65,980 new cases and 19,500 deaths occurring in 2009. The histological subtypes of NHL fall into two major classes: indolent (slow growing) and aggressive (fast growing). Lymphomas with indolent histologies include B-cell follicular lymphoma, marginal zone lymphoma, small lymphocytic lymphoma, and cutaneous T-cell lymphoma. Lymphomas with aggressive histologies include diffuse large B-cell lymphoma, lymphoblastic lymphoma, and Burkitt lymphoma. Mantle cell lymphoma is classified as an aggressive lymphoma but possesses characteristics of both indolent and aggressive disease.

Treatment of indolent NHL depends on the histology and stage of the disease. Because indolent NHL is often asymptomatic in early stages, it is generally advanced (stage III or IV) at the time of detection. Treatment for indolent NHL typically involves a combination of chemotherapy and immunotherapy, such as cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) plus rituximab. Alternatively, other chemotherapy regimens may be used in combination with rituximab, including cyclophosphamide, vincristine, and prednisone and fludarabine-based regimens. Radiation and bone marrow or stem cell transplantation are treatment options in selected patients.

Indolent NHL is generally incurable. Patients typically follow a course of remission and relapse requiring multiple rounds of therapy with rituximab, chemotherapy, or both. Eventually, most patients become refractory to chemotherapeutic agents, rituximab, or both.[20] Therefore, new treatments are needed to prolong the duration of remission and overall survival for patients with relapsed and refractory indolent NHL.

Bendamustine is useful in that it shows little cross-reactivity with common first-line indolent NHL therapies. It is effective in patients refractory to rituximab, chemotherapy, or both...”

What about side effects?

“Bendamustine is generally well tolerated. The most common serious (grade 3 or 4) adverse events are hematologic in nature. Gastrointestinal events are also commonly observed but are usually mild to moderate in severity. Adverse events can often be managed with supportive therapies or dosage modifications.”

Translation: like other chemotherapy agents, it can throw your blood counts out of whack and it can make you vomit. Yet, they say these side effects can be pretty much kept under control with other drugs.

In the oncologist’s lexicon, “well tolerated” doesn’t mean you feel good. It means the doctors don’t usually have to cancel the chemotherapy because it’s making you so sick you can’t stand it.

In any event, this is another bit of encouraging news for me, for whenever it should happen that “watch and wait” ends and “go and do something” begins.

It’s good to have more than one arrow in the quiver, to be sure.

July 22, 2009 - Dulanermin

Paging through an old copy of Cure magazine (a publication for cancer survivors), I notice a headline in a full-page ad: “Have you been diagnosed with Follicular Non-Hodgkin’s Lymphoma (NHL) following previous rituximab therapy?”

“That’s me,” says I to myself.

Reading on, I discover it’s an ad for a clinical trial being conducted by Genentech – the drug company that brought us rituximab (Rituxan). They’re also the people who flew Claire and me to Las Vegas a few years ago, to give a little motivational talk to their sales force.

Down at the bottom is a serial number I can use at the clinicaltrials.gov website, to find out more about this study.

I visit that site, key in the number, and come up with a page describing a study of a new investigational drug called Apo2L/TRAIL – trade name, Dulanermin.

It’s a Phase II clinical trial – which means it’s still in the early stages of investigation. As of now, the trial is also fully subscribed: which may be just as well, since I’m not sure I’d want to risk the side effects of a Phase II trial when I’m still in a watch-and-wait mode and feeling good.

It’s interesting to read about this new drug, all the same, because it could be in my future.

Here’s the scoop, from an Amgen press release of a couple months ago (the Amgen pharmaceutical company is conducting this research in partnership with Genentech). Dulanermin is one of a family of “highly selective therapies to induce cancer cell death.” Well, who can argue with that?

“In cancer,” the article continues, “the dysregulation of apoptosis is critical in the development and survival of tumors.” I know, from previous reading, that apoptosis is cell death – the normal tendency of cells to die according to a genetically-preset timetable, only to be replaced by new cells. In cancer cells, the apoptosis switch is turned off, allowing them to continue to grow and wreak havoc in the body. “The dysregulation of apoptosis” is inscrutable medical jargon for “throwing a wrench into the genetic machinery that would otherwise cause cells to die when they reach the end of their natural lifespan.”

Dulanermin – if it fulfills the hopes of the pharmaceutical researchers – would yank that monkey-wrench back out of the machinery, so cells would continue to die according to their normal timetable and would never morph into cancer cells.

The article defines dulanermin as “a recombinant human protein that targets death receptors 4 and 5.” Sounds like something out of Star Wars: “Luke, your mission is to fly your X-fighter along the surface of the Death Star and take out death receptors 4 and 5. May the Force be with you.”

Go for it, Luke.

Is this the next Rituxan? Impossible to say. Clinical trials like this are being conducted all the time, mostly below the radar of non-medical types like me. Every once in a while, a full-page ad jumps out at us, a reminder that this valuable work is going on.

Kudos to the researchers for keeping up with this sort of thing.

Who knows? If this one ever makes it to a Phase III trial, maybe they can sign me up.

June 14, 2009 - New Lymphoma Vaccine

I’m feeling hopeful, today, after reading some articles about a new vaccine for follicular lymphoma, recently announced by Dr. Stephen Schuster, of the University of Pennsylvania’s Abramson Cancer Center, at the American Society of Clinical Oncology’s annual meeting in Orlando. One article is a University of Pennsylvania press release, the other an ABC News story.

Dr. Schuster’s study involves a personalized cancer vaccine, fabricated out of the patient’s own malignant cells. Other cancer vaccines are created to go after some factor that influences the survival of cancer cells. This one is different, Dr. Schuster says, because it goes after the cancer itself. The vaccine – or, rather, the process of producing it, since every patient’s version is different – is called BiovaxID.

I suppose it’s kind of like giving a bloodhound an article of clothing belonging to the fugitive being tracked. Having memorized the criminal’s distinctive scent, the hound is able to sniff out the quarry. The cancer vaccine, equipped with chemical markers from the patient’s malignant cells, does much the same thing.

The vaccines, which take 3 months to produce, are given in 5 injections spaced over 6 months.

The vaccine was given to follicular lymphoma patients who had received the standard CHOP chemotherapy treatment (the same one I had, minus the Rituxan), and who had gone into a remission lasting longer than 6 months (mine lasted 8 months). Those patients in the trial who received BiovaxID did significantly better than those in the control group: 44.2 months without a relapse, on the average, for those in the vaccine group, as compared with 30.6 months for those in the control group.

Dr. Schuster is calling for a new clinical trial, to see how the results will come out for those treated with R-CHOP (CHOP + Rituxan), as I was.

I wonder how long it will be before the vaccine is available, outside of clinical trials. I wonder, also, to which patients it would be given: whether only to people like those in the clinical trial, who are still in remission after treatment, or to people like me as well, who are out of remission. (Then again, maybe it could help me after my watching and waiting time is over, and some other treatment puts me back into remission.)

Complicated questions, to be sure. Regardless, news like this is always a source of hope.

March 9, 2009 - More Questions About Maintenance Rituxan

Steve, a reader of this blog, reminded me of a 2006 European study that found “dramatic” results in follicular NHL patients who were receiving maintenance Rituxan treatments. Unlike the one I cited yesterday, this study includes patients who have received R-CHOP.

Those patients in the study who received R-CHOP, and who subsequently received maintenance Rituxan, experienced an average of 52 months without their disease progressing – as opposed to 23 months in the control group. That’s more than double the time.

That raises a lot of questions for me. My disease has already returned, but it’s not doing much of anything. Every time I go for a scan, the verdict is, “Still there, but no bigger.” Dr. Lerner has me on “watch and wait,” the reasons being that (1) my slightly enlarged, malignant lymph nodes are doing no immediate harm, and (2) when they get large enough to treat, there’s a high likelihood that a second round of chemo will put me back into remission (and, if I receive a stem-cell transplant instead, there’s even the possibility of a cure).

I don’t know whether starting on Rituxan-only treatments is still an option for me, at this stage – everyone in the research studies presumably began receiving them right after their chemo. Even if maintenance Rituxan is still available to me (and if we could convince the insurance company to fund it), I’m still not sure it’s the best idea. Dr. Lerner’s cool-under-fire strategy of waiting till we see the whites of their eyes before we start blasting away appeals to me.

Questions, questions. What if? When? Why? Why not? You never get away from the questions, when you’re a cancer survivor.

“Wait for the Lord;
be strong, and let your heart take courage;
wait for the Lord!”

– Psalm 27:14

March 8, 2009 - The Treatment I Didn't Get

Today I run across a Reuters news article about rituximab (trade name, Rituxan), the monoclonal antibody drug I received along with my chemotherapy. It seems a research study has just demonstrated good results for “maintenance therapy” with Rituxan – in other words, continuing treatment with the drug over time, even after the cancer has gone into remission:

“An improved disease response was seen in 22% of rituximab-treated patients versus just 7% of control subjects....

Three-year progression-free survival was also higher in the rituximab group: 68% vs. 33% in controls. In the subgroup of 282 patients with follicular lymphoma, the corresponding rates were 64% and 33%. Higher overall survival rates were seen in the rituximab group as well, although the differences fell short of statistical significance....

‘Observations from this study inform the design of future studies and add to a substantial body of evidence that the combination of rituximab with chemotherapy is a new standard for patients with indolent lymphoma who require treatment,’ the authors conclude.”

At the time my R-CHOP chemotherapy ended (the “R” in R-CHOP stands for Rituxan), I was aware that some patients were continuing to receive monthly treatments with Rituxan for a year or more, as a preventative measure. This was, and continues to be, somewhat controversial. At several NHL patients’ conferences I attended, the medical experts making the speeches said the jury was still out on whether or not maintenance Rituxan does any good. With the tremendously high cost of this medication, many medical insurers had labeled it “experimental,” and were not funding its use in maintenance treatment. (I never took the matter up with my insurance people, because Dr. Lerner didn’t recommend maintenance Rituxan in my case.)

Well, now the jury has filed back into the courtroom and delivered their verdict: maintenance Rituxan does work – at least for indolent NHL patients who have had the CVP chemo regimen (cyclophosphamide, vincristine and prednisone). The researchers didn’t focus on patients who’ve had the CHOP chemo cocktail, rather than CVP – although, since vincristine and prednisone are two out of the four drugs in CHOP, I would think there’s a pretty good chance maintenance Rituxan would have improved my long-term prognosis, as well.

This raises a lot of unanswered – and probably unanswerable – questions for me. Chief among them is, if I had received maintenance Rituxan, would my remission have lasted longer than it did?

Hindsight, as they say, is 20/20. I’m not going to run off and ask Dr. Lerner about maintenance Rituxan now, but it does give me something to think about. Maybe I'll ask him what he thinks of this article, next time I see him...

September 3, 2008 - Another New Cocktail

No, I’m not talking about some concoction served in an umbrella glass, under a buzzing neon light. I’m talking about a new combination of anti-cancer drugs that may help certain lymphoma patients.

“Novel Clinical Study For Lymphoma Patients Beginning,” reads the headline of yesterday’s internet news article. It heralds a clinical study, investigating whether patients receiving a new combination of two chemotherapy drugs will do better than those receiving more conventional treatments. The drugs are for patients with diffuse large B-cell or mantle-cell lymphoma. Diffuse large B-cell was the aggressive type of cancer I had, which has (fortunately) not come back since my R-CHOP chemo treatments in the spring of 2006. If it ever comes back, I could potentially benefit from tossing back a few of these new cocktails (well, not literally tossing them back; they’d be delivered through IV tubes).

The drugs being studied are bortezomib, marketed as Velcade, and vorinostat, marketed as Zolinza. (Where DO they come up with these crazy names?) Bortezomib – a comparative old-timer in the world of cancer drugs – has been around since 1995, and vorinostat is a newer drug, approved by the FDA for treatment of another type of lymphoma (cutaneous T-cell) less than two years ago.

These types of clinical trials go on all the time. This one’s a phase II trial, one of the riskier varieties. As I understand it, phase I trials are truly experimental – only the sickest patients get these drugs, the unfortunate souls for whom nothing else is working. Based on experiments with laboratory animals (the proverbial “guinea pigs,” whether or not they actually belong to that species), the scientists are reasonably sure the drug will help humans, but they can’t be absolutely sure. So, they pick a few people who have no other choices, give them the new drug, then sit back and watch what happens.

If the experimental subjects do better than expected, the scientists move on to phase II. They’re still working with a relatively small group of desperately ill patients, but this time they’re trying to figure out the dosage. In this stage, patients sometimes experience severe side effects, as the experts try to get the dosage right. Neither phase I nor phase II trials are a walk in the park for the volunteers who participate in them – although they’re usually willing enough to take the risk, because they have few other alternatives.

If the signs continue to be good, the researchers move on to a stage III trial. By now, they know the drug works, but they need hard data comparing it to other drugs. This is the sort of trial that involves thousands of patients all over the country (or even the world). It includes randomization – there is a randomly-selected control group of patients, who are given some other, more established drug instead of the one being studied. (In cancer trials, placebos are rarely given to the control group, for ethical reasons.)

If the new drug makes it through this third gate, it will probably receive FDA approval. The company then dispatches its eager sales force out to doctors’ offices, with their free pens and sandwich trays for the office staff. After the drug is out there for a little while, stage IV trials follow, as the benefits and side-effects of the treatment protocols are studied further, over time.

Speaking as a cancer survivor, it’s encouraging to read of new developments like these. I’m glad the pharmaceutical researchers are out there, dripping fluids from eyedroppers into petri dishes, or whatever they do. It’s a long road, from the genesis of an idea in a laboratory to a chemo nurse hanging a bag of the stuff on an IV pole. Drug companies have to put up millions of bucks before they see a penny of profits, and for every drug that makes it into production, many more die on the vine, never making it out of stages I or II.

Will I ever receive this yet-unnamed drug combo? Who’s to say? It just goes to show how dynamic and uncertain the field of cancer treatment continues to be. I’m in a slow, watch-and-wait mode right now. It’s remarkable – and scary – to think that the drug that could help me one day may still be in the early theoretical stages, years away from production.

We live with that uncertainty, and with that hope.

July 10, 2008 - Loss of Control

A friend of ours, Mary Beth, sent me a link to a doctor’s blog, “Musings of a Distractible Mind,” by Dr. Rob, an internal medicine doctor from the Southeastern U.S. It’s an insightful and witty blog – well worth a visit.

I was interested in a post, “Dangerous Information,” from June 25th. In it, Dr. Rob engages in a good-natured rant about patients who habitually question the prescriptions he writes:

“A patient left me a message earlier this week: ‘I was reading the information on the drug that Dr. Rob prescribed, and I am really worried about it.’ He went on to say he was faxing me the prescribing information, just in case I didn’t realize the risk of the medication.

I hate it when people do this. Do they realize that I studied for eight years and have practiced another thirteen? Why would I prescribe something for them that I don’t know about? Why would I put my name behind a ‘dangerous’ prescription? Why would they bother coming to me if they thought I did not know these things?

I don’t really take it as a personal insult, and I do feel that it is fine to question the doctor. I am sure it has happened that I have given prescriptions with interactions and/or side effects that I did not think of, but there are some levels of questioning that cross the line. I am an internal medicine doctor, so medications are my tool. Would you ask a surgeon, ‘Are you sure you should make a midline incision? Do you think that a lateral approach may be better?’ Do you tell a cardiologist, ‘I read on the Internet that the non drug-eluting stents are better than the drug-eluting ones’? Do you ask the radiologist, ‘Don’t you think that density could represent pleural plaque rather than an infiltrate?’ Probably not.”

I posted this comment in Dr. Rob’s blog:

I’m not sure most patients who question doctors’ prescriptions do so because they don’t trust the doctors. I think they do it for the same reason so many people are obsessed finding that miracle food (or avoiding that dangerous food) they imagine will prevent cancer. It has to do with loss of control.

Unlike submitting to a surgeon’s decision on where to place the scalpel, popping a pill into our mouths is something we do have some small measure of control over. And so, some of us hang onto that tiny shred of control, even if it makes our doctors suspect, sometimes, we have no confidence in them.

A great many illnesses happen regardless of how we choose to live our lives: and that truth is a hard one to absorb. We like to imagine the world is a fundamentally safe place for people who work hard and try to do the right thing, when in fact it’s not. Bad things do happen to good people. Most of us would rather cling to the illusion that we are masters of our own destinies.

I've got non-Hodgkin lymphoma, a disease for which there are few known environmental or inherited causes. Some unlucky people just get NHL, and medical science doesn’t know why. A cancer like mesothelioma isn't like that. Most cases of that disease, I've read, result from asbestos exposure. Luck has nothing to do with it (unless you count the decision to take a job in an insulation factory in the 1960s a matter of bad luck). The same goes for people with leukemia who were living downwind from Chernobyl when that nuclear power plant melted down. A person with asbestos-related or radiation-related cancer knows exactly where it came from. And there’s some small - admittedly, VERY small - comfort in that.

So, next time one of your patients brings in some article from a wacky natural-health magazine about the benefits of some cactus extract, or starts questioning whether the prescription you’ve prescribed safely for hundreds of patients could make them sicker, consider this: it may be because your patient is struggling to absorb the harsh truth that some sickness just happens.

Cancer is a scary thing. That’s why the field of cancer treatment is a congenial playground for all manner of charlatans and quacks – and why so many cancer patients are so easily bamboozled by them. Yes, it’s a very good thing for us to educate ourselves, becoming as well-informed as we possibly can. Yet, let us also remember, as we scan the Internet, that doctors who have studied long and hard to learn about our condition are our best, most trustworthy advisors.

Thanks, Mary Beth, for the link to this excellent blog. And thanks, Dr. Rob, for getting me thinking about this.