Thursday, December 01, 2005

Zometa, IGG's, and Physical Therapy, but Feeling Well

Ah, the long awaited doctor's visit. The white cells, although down a bit, are fine, red cells are up and platelets are way up. I received an IV of zometa today, which is a bone strengthening drug. Much more info on zometa is set forth below. The infamous IGG's are unfortunately trending UP, not Down. Went from 2440 to 3200. But my doctor was adamant that I should not concern myself with this, as there are way too many factors that could account for this...including the fact that my body is producing good immunoglobulins which could be counted in this number. He plans to do a much more definite and comprehensive blood test next visit (but not a bone marrow biopsy). Notwithstanding his dismissal of these numbers, I was disappointed as I know he would liked to have seen a downward, not upward trend. I did pull one of the nurses aside after I received the IV of zometa and grilled her a bit more on the numbers. She, who is a straight shooter, also told me they have many patients whose numbers don't move downward after transplant but they are able to control their myeloma with maintenance drugs. It would not surprise me to be put back on the steroid, dexamethasone, which was very effective in my early treatment in bringing the IGG's way down. I don't particularly like my body's response to the dex (shakes, and irritability), but it was quite effective. There is apparently a study by the French that shows this to be an effective measure following transplant. Ah, it is the acceptance of the fact that this is a long voyage that is so difficult at times. I am also going to start physical therapy for my back to relieve some of the stiffness and can return to the health club to try to get back into shape (staying out of the hot tub and pool). I also am likely to have my prostate surgery within the next month or so. Dr. Rifkin asked that I get back in touch with my urologist and get that going. He suggested we might try to do that around the same time as the restaging (bone marrow biopsy, etc.) So, it looks like the holidays may be busy. But I feel better every day and now that I can start working out and going to physical therapy I will probably start feeling even better. Today feels like one of those difficult days. But Susan refuses to be lead down the negative path--"I know you'll be fine and you can't pay attention to those numbers", she tells me. So, I will accept that approach--after a good night's sleep. Next visit is December 14th.

Zometa (zoledronic acid)
What It Is
Zometa® (zoledronic acid) is an intravenous, nitrogen-containing bisphosphonate marketed by Novartis Pharmaceuticals. It was initially approved in the US in 2001 for the treatment of hypercalcemia of malignancy (HCM), also known as tumor-induced hypercalcemia (TIH). It was approved in 2002 for the treatment of bone lesions in myeloma and patients with documented bone metastases from solid tumors, in conjunction with standard cancer therapy.

Zoledronic acid is 100-fold more potent than pamidronate. Because of this fact, the dose of zoledronic acid required is substantially lower and can be administered in a shorter period of time than pamidronate (15 minutes versus 2-4 hours).
What It Does
Zoledronic acid inhibits bone resorption, which is the breakdown of bone by osteoclasts. Although the exact mechanism of action is not completely understood, several things are thought to occur. In the laboratory, zoledronic acid inhibits osteoclast activity and induces apoptosis (programmed cell death) of osteoclasts. It also binds to bone and may block resorption. In addition, zoledronic acid inhibits the increased osteoclast activity and skeletal calcium release induced by various stimulatory factors released by tumors.
How It Is Administered
Zoledronic acid is administered as an intravenous infusion. The recommended dosage in patients with myeloma is 4 mg administered as a 15-minute infusion, given every 3 to 4 weeks. The optimal duration of therapy is not yet known. However, in clinical studies in myeloma, patients were treated for up to 12 months, and patients have received the drug for longer periods of time. Data from long-term administration (24 months of therapy) have been submitted to the regulatory authorities.

Patients receiving zoledronic acid should also take an oral calcium supplement of 500 mg and a multiple vitamin containing 400 IU of vitamin D daily.

Benefits in Myeloma
Zoledronic acid has been shown to be more effective than pamidronate in normalizing serum calcium levels in patients with hypercalcemia of malignancy. In 2 studies that were analyzed together, zoledronic acid (4 mg) normalized calcium by day 10 in 88% of patients compared to 70% with pamidronate. In addition, the median duration of response was significantly longer with zoledronic acid (32 days compared to 18 days). (Major et al. J Clin Oncol. 2001;19:558-567.)

In patients with myeloma, various studies have shown that zoledronic acid is as effective as pamidronate in treating bone lesions. For example
Zoledronic acid and pamidronate each reduced the number of skeletal events and the need for radiation therapy to bone in a study of patients with myeloma. (Berenson et al. Cancer. 2001;91:1191-2000.)
Results of a Phase III trial comparing zoledronic acid and pamidronate showed equal efficacy and tolerability of the drugs in the treatment of bone lesions in myeloma and breast cancer over the period of 1 year. (Rosen et al. Cancer J. 2001;7(5):377-387). Long-term (25 month) data from the study showed that both agents reduced the overall proportion of patients with a skeletal event. However, compared with pamidronate, zoledronic acid reduced the risk of developing skeletal complications (including hypercalcemia) as determined by multiple event analysis by an additional 16%. In patients with breast cancer, zoledronic acid was significantly more effective than pamidronate, reducing the risk of skeletal events by an additional 20% compared with pamidronate and by an additional 30% in patients receiving hormonal therapy. (Rosen et al. Cancer. 2003;98(8):1735-1744.)
Results of a small Phase II study in elderly patients with symptomatic refractory myeloma showed that the combination of zoledronic acid and targeted radiotherapy (Quadramet® [Samarium Sm-153 lexidronam], Cytogen) was an effective palliative option. For the eight patients in the study, one to three courses of therapy with these two agents was sufficient to produce long-term improvement in symptoms, particularly bone pain. (Iuliano et al. J Clin Oncol. 2004;22(14S). Abstract 6737.) Patients received a standard dose of 4 mg of zoledronic acid every 4 weeks and slightly more than half of the standard dose of Quadramet. No severe adverse effects were noted; two patients experienced transient grade 2 hematologic toxicity. Interestingly, M-protein levels decreased more than 25% in 4 out of the 8 patients and were still stable at 19 months follow up.
• Get more information on bone disease in myeloma
Guidelines for Use of Zometa in Myeloma
In September 2002, the American Society of Clinical Oncology (ASCO) published clinical practice guidelines for the use of bisphosphonates in the prevention and treatment of bone disease in myeloma. (Berenson et al. J Clin Oncol. 2002;20:3719-3736.) Upon review of published literature, the expert panel agreed that bisphosphonates reduce skeletal complications and provide a meaningful support benefit to myeloma patients with bone disease.

For patients who have bone lesions or bone loss, the guidelines recommend the use of intravenous zoledronic acid (Zometa) 4 mg infused over 15 minutes or pamidronate (Aredia®) 90 mg infused over 2 hours every 3 to 4 weeks. These bisphosphonates may also be used as part of a pain management strategy. The guidelines recommend that therapy, once started, be continued until the likely benefit is believed to be less than the inconvenience of receiving the treatment or until significant side effects are experienced.
• Get the complete summary of the guidelines for bisphosphonates
Potential Antitumor Effects
Zoledronic acid also appears to have several potential antitumor effects. For example,
It reduces the secretion of the growth factor interleukin 6 (IL-6) by myeloma cells grown in the laboratory. IL-6 is known to play an important role in the growth and survival of myeloma cells
In laboratory studies, zoledronic acid inhibited growth and induced apoptosis (programmed cell death) in human myeloma cell lines
Zoledronic acid exerted antimyeloma effects in mice that had implants of human myeloma cells growing in human bone fragments. (Yaccoby et al. Br J Haematol. 2002;116(2):278-290.)
When combined with dexamethasone in the laboratory, the effect of zoledronic acid on inhibiting growth and inducing apoptosis of myeloma cells was enhanced. (Tassone et al. Leukemia. 2000;14:841-844.)
The drug inhibited angiogenesis (the growth of new blood vessels) in an animal model. (Wood et al. Proc 36th ASCO Annual Meeting, New Orleans. 2000;19:664a.)
It is able to prevent the development of bone disease in a mouse model of myeloma. In this model, treatment with zoledronic acid was associated with a decrease in tumor burden and a significant increase in disease-free survival. (Croucher et al. J Bone Miner Res. 2003;18(3):482-492.)
Zoledronic acid appears to affect bone marrow stromal cells taken from patients with active myeloma, which could contribute to its antitumor effects. In the lab, the agent reduced bone marrow stromal cell proliferation, increased apoptosis, and modified the expression of adhesion molecules on their surface. (Corso et al. Blood. 2003;102(11). Abstract 1619.)
In blood cells taken from patients with myeloma, zoledronic acid induced anti-myeloma activity by activating a particular type of T cell. Zoledronic acid also enhanced the sensitivity of myeloma cells to killing by these T cells. (Mariani S et al. Leukemia. 2005 Mar 3. [Epub ahead of print])
However, it is not known whether zoledronic acid has the same effects in patients with myeloma.
Potential Side Effects
Zoledronic acid is generally well tolerated and the side effects are similar to those seen with pamidronate. Some patients may experience mild and transient side effects, such as fever, flu-like symptoms, fatigue, gastrointestinal effects, or anemia, which may be related to their underlying disease. Although rare, long-term use of the drug at higher doses or zoledronic acid infused in less than
15 minutes can affect the kidneys. For this reason, patients who receive zoledronic acid should have serum creatinine assessed prior to each treatment. In addition, serum calcium, electrolytes, phosphate, magnesium, and hematocrit/hemoglobin should also be monitored regularly.

Upon treatment initiation, dosage adjustments are recommended in myeloma patients with mild or moderate kidney impairment. (See How It Is Administered.) Treatment with zoledronic acid is not recommended in patients with severe kidney impairment because studies in this patient population have not been conducted. In myeloma, the risk of kidney dysfunction may be increased when it is used in combination with thalidomide or drugs known to affect kidney function (ie, nonsteroidal antiinflammatory drugs). There are animal data to suggest there can be a problem when bisphosphonates are administered during pregnancy. Therefore, zoledronic acid should not be used during pregnancy unless a physician feels the benefits outweigh the risks.

Long-term therapy with zoledronic acid appears to be safe. Results of a recent study of 22 patients who received intravenous zoledronic acid or pamidronate for up to 6 years found that prolonged therapy was well tolerated. No significant calcium, phosphorus, electrolyte, or WBC count abnormalities were seen. A clinically insignificant decrease in hemoglobin and platelet count and an increase in creatinine were observed. There were no stress fractures of long bones with prolonged therapy and the fracture rate beyond 2 years was no greater than during the first 2 years of treatment. (Ali et al. J Clin Oncol. 2001;19:3434-3437.)

A number of cases of painful exposed bone in the jaw (a condition called osteonecrosis of the jaw) have been reported in patients receiving intravenous bisphosphonates (pamidronate or zoledronic acid) for hypercalcemia of malignancy related to myeloma or breast cancer. (Marx RE. J Oral Maxillofax Surg. 2003;61:1115-1118.) However, cancer patients in general are at increased risk for this condition due to other therapies they may receive, such as radiation, chemotherapy, and medications such as steroids. (Tarassoff P. J Oral Maxillofax Surg. 2003;61:1238-1239.) Although no cause and effect relationship between bisphosphonates and osteonecrosis has been established, it is recommended that cancer patients take adequate steps to maintain their oral health. This includes practicing good oral hygiene and scheduling regular dental visits. Patients may want to complete major dental procedures before they begin treatment with bisphosphonates. If a dental problem does occur, the least invasive conservative management strategy is preferred.
Ongoing Clinical Trials
Trials are evaluating the use of zoledronic acid as an integral part of a treatment regimen for patients with early-stage or newly diagnosed myeloma to see if it can help prevent or delay the development of bone lesions. An additional trial is being conducted to determine the effect of zoledronic acid on the bone density of patients with bone loss with monoclonal gammopathy of undetermined significance (MGUS).

A study is also being conducted to investigate if lengthening the duration of infusion, in conjunction with increased volume of liquid the zoledronic acid is administered in, will provide renal protective effects.

The combination of zoledronic acid and the targeted radiotherapeutic Quadramet® (Samarium Sm-153 lexidronam, Cytogen) is being evaluated for the treatment of pain associated with metastatic bone disease in patients with recurrent or refractory myeloma.

Ongoing zoledronic acid clinical trials in myeloma are listed in the table below.

Ongoing Zometa Clinical Trials in Myeloma as of May 2005
Phase IV
A Multicenter, Open-Label, Randomized trial evaluating the duration of infusion of Zometa (zoledronic acid) 4 mg IV in Multiple Myeloma Patients with Bone Metastases
• View trial information
UARK 2004-43, A Multicenter, Open-Label, Randomized trial evaluating the duration of infusion of Zometa 4 mg IV in Multiple Myeloma Patients with Bone Metastases
• View trial information

Phase III
A Phase III Randomized Trial of Thalidomide plus Zoledronic Acid versus Zoledronic Acid Alone in Patients with Early Stage Multiple Myeloma
• View trial information

Phase II
First-line Treatment of Newly Diagnosed Multiple Myeloma with Combination of Low Dose Thalidomide, Zometa, and Dexamethasone
• View trial information

Phase I/II
A Phase I/II Trial of Zometa in Patients with Monoclonal Gammopathy of Undetermined Significance (ZOMGUS-001)
• View trial information


Dorothy said...

Hello Pattersons. It sounds as though you had a very nice Thanksgiving, that is wonderful. Dan, the voyage is long and incredibly frustrating but you are doing so well. Keep up the positive attitude and try so very hard to have patience! It is easy for us who do not have to go through your day but patience is what is needed.

We returned from Germany on Monday and we had such a great time. It was especially nice to know that I completed my Masters Program and could just relax there and when we got home. I really don't feel or look any "smarter".

Needless to say I entered into many conversations with people in Germany regarding our "esteemed" leader with many who had the same opinion as I!! So you can imagine how I talked that up to Greg!! I do believe he is coming around to the "sane" side of this whole mess.

Take care and love to Susan, Catherine and Julia. The Seals

sigunjoe said...

Dear Dan,

I know you were disappointed about the numbers, but I have to say that I do love your doctor's upbeat attitude; he knows what he is talking about; and the nurse as well. So, as Dorothy just said, have patience. I know you will. You are the most patient and positive guy I know!

Thanks for all the info on Zoledronic. Thank God you are not pregnant -- otherwise you could not take it!

Am sending many good thoughts and all my love. Sigun.

Dan's Mom said...

I had to take a couple of Tums in order to digest all that information. But I got a positive feeling after reading it. Just listen to your doctor who seems positive and to Susan. I know it is a long and hard battle but we are all with you all the way. You should feel great waves of love and encouragement coming your way. Just relax and let them wash over you. Much love and encouragement from your mom. Dan's Mom

Patty Nelms said...

Well...numbers, schnumbers! I can feel your disappointment and that makes my heart sad simply because I know how hard you're working to heal yourself. That's all it is though is numbers. None of these tests can measure the light and love that is you and as far as I know, that's all that matters. Keep your chin up. You've come so far and you've done it with incredible grace and dignity. Just one day at a time, Dan. You are entitled to have a pissy day too. Just have Susan call and I'll come and haul you off for the day because you know it'll only crack me up!!

Keep up the great work! Do you know about the collective worldwide meditation beginning Dec. 21-31? I'll tell you more next time I see you. What a powerful thing that'll be!!

Have a lovely day and don't worry! Hi to Julia, Catherine, and Susan!!
Love, P

Tom said...

Go with the qualitative over quantitative everytime. You are on the path - keep with it: you've got lots of support - let it steer you onward.

We've had snow and snow and then more snow here in Spokane (it's snowing now as I write).

And now a wonderful poem by Wislawa Szymborska to reflect on, in view of our last conversation and the vicissitudes of this place we're in:



Island where all becomes clear.

Solid ground beneath your feet.

The only roads are those that offer access.

Bushes bend beneath the weight of proofs.

The Tree of Valid Supposition grows here
with branches disentangled since time immemorial.

The Tree of Understanding, dazzlingly straight and simple,
sprouts by the spring called Now I Get It.

The thicker the woods, the vaster the vista:
the Valley of Obviously.

If any doubts arise, the wind dispels them instantly.

Echoes stir unsummoned
and eagerly explain all the secrets of the worlds.

On the right a cave where Meaning lies.

On the left the Lake of Deep Conviction.
Truth breaks from the bottom and bobs to the surface.

Unshakable Confidence towers over the valley.
Its peak offers an excellent view of the Essence of Things.

For all its charms, the island is uninhabited,
and the faint footprints scattered on its beaches
turn without exception to the sea.

As if all you can do here is leave
and plunge, never to return, into the depths.

Into unfathomable life.
Love - Tom

sigunjoe said...

Dear Dan,

I was thinking of you yesterday when walking by the Jardin du Luxembourg. I know you liked to sit on one of the benches, watching people go by.

We went to the Duncan Phillips exhibit at the Musee du Luxembourg yesterday. What a splendid collection that is. Have you ever seen it in Washington? Apparently the collection is housed in the private mansion of Mr. Phillips. What good taste he had. I especially loved the huge painting by Renoir entitled, I believe, 'Dejeuner des Canotiers', a group of people having an outdoor lunch; just so full of life and light, it really picks you up.

On our way home we stopped off at Poilane for half a huge bread, then walked on the rue de Sevres. There, in front of a store, I saw the ugliest Christmas decoration ever: a blue Christmas tree, with blue lights. I have seen trees sprayed with a kind of foam in white, or worse, in red, but this blue, it was the pits. I must say that the Champs-Elysees look nice with all the little lights in the trees, and I know that I will enjoy the windows of the Grands Magasins (especially the ones of Galleries Lafayette), but I must say that in general, the French are not gifted for beautiful Christmas decorations. One day you guys should go to Germany; every town, big or small, is beautifully and tastefully decorated.

Tonight we are going to the monthly Democrats Abroad dinner at a restaurant near the Bourse called 'Les Noces de Jeannette' (funny name; it means the Marriage of J.). A political science professor at Williams College will speak on the political situation. Will report what he says!

Keep well and get strong. Bises, Sigun.

sigunjoe said...

Dear Dan,
Reading the Zometa detail, as your mother so wittily puts it, makes one reach for the Tums. It also makes one realize how the impulse to know everything, which I hope I would have the courage and energy to pursue were I the patient, comes with its down side. Even though much of the detail will not affect you, knowing it opens you up to such a wide range of imaginings. On the up side, it seems that this rigorous process is a fine way to build your confidence in your doctors, something which obviously has been happening. Doctors who are either too busy to explain in detail, or worse, vague on some if it, do not seem to be getting near you.
The other evening, Sigun and I attended the first-Tuesday-of-the-month dinner of Democrats Abroad, which is not only a wonderfully gassy balloon of speeches, passionate declarations and fevered denunciations, but a formal caucus of the Democratic Party. Sometimes the speaker is good, sometimes very good. This one, George Marcus, a professor of politics at Williams College, was very good. He spoke about what precisely it is that wins elections. He spoke with real authority because he did so much of the research on the subject himself. And he said some things that were, on their face, incredible, and on further thought, persuasive.
Marcus argues that presidential elections are won when one candidate gets more votes from the opposing party’s registered voters than his opponent manages to steal from the other side. Debates don’t count. Independent voters don’t count. Strong partisans and what he calls “leaners” are what count.
In the 1980 election, for instance, the polls showed that 20% of strong Democrats and 44% of Democrat leaners were prepared to vote for Reagan. Only 16% of strong Republicans and 26% of Republican leaners were prepared to vote for Carter. In 1984 30% of strong Dems and 34% of Dem leaners were prepared to go with Reagan, contrasted with 10% of strong Republicans and 16% of GOP leaners set to go for Mondale.
Defections are the key. In 2004, Kerry won 48% of the independent vote. But while 11% of all Democrats voted for Bush, only 6% of Republicans voted for Kerry.
So the big question is: when and why do partisans defect? While the specifics vary—personality of candidates, money in the campaign, war, the economy and so on—the single overarching factor in defections is when the incumbent (not his opponent, just the incumbent) makes people anxious. When people are complacent, they will vote their partisanship. When we sense that something is wrong, we no longer rely on habits and we’ll start listening to the other side.
I can hear you now, Dan, taking up the prosecution side in this case. How on God’s earth could voters not have been made anxious by Bush’s first-term performance, in terms of both the domestic economy and the conduct of the war in Iraq?
Remember, we are not talking about the people who don’t defect, only those who do. And the point about the 2004 election that Marcus says is key is that fewer people defected from Bush than from Kerry. Among these, ideology has no effect on their vote. Anxiety creates the opportunity for one party to paint its candidate as the “better guy,” as Marcus puts it. And the Republicans were successful in this by creating a sense of hyperanxiety about homeland security. This even trumped the anxiety over Bush’s handling of the economy, on which Kerry won big. It was no coincidence, Marcus says, that Tom Ridge, the homeland security secretary, was issuing red and amber alerts throughout the campaign. And Karl Rove’s single megamessage was: Bush has prevented any more 9/11s. You’re safe with him. You won’t be safe with Kerry.
On the other side, Kerry’s message was: our plan on Iraq and terrorism at home is pretty much the same as Bush’s. We’ll just do it better. So, asks Marcus, why should voters go for Mr. Me-Too when they can stick with the guy they have? Bush made them feel comfortable with his war-president stewardship and uncomfortable with Kerry. The swiftboat veterans deepened this feeling. Marcus made an interesting psychological point here. Bush created fear. When we re afraid we become rational, in the sense that we start weighing things. I have a feeling, Dan, that these psychology points are standard fare for a seasoned defense attorney like you.
Marcus reiterated here that making people more anxious about the incumbent is far more powerful than making them anxious about the opponent. And this is where Kerry seemed to fall woefully short. He was struggling to make people comfortable with the notion of him as commander in chief. This strategy was just steamrolled by the Bush one-note barrage.
I asked Marcus which is the more powerful emotion in all this, dislike for one candidate or enthusiasm for the other candidate? (My belief is that resentment has been the most powerful factor in politics, the essential energy of the left, from the French Revolution on.) Marcus responded by saying that people vote for one of two reasons:
1) you vote for the one you like better (the good guy); or
2) you vote against the one you despise. He also made the interesting point that people who are angry about something or someone are not willing to listen to any counter-arguments. One example he gave from 2004: gay rights. “If you want people to stay the course, make them angry,” he said. This also reveals the marketing strategy of Rush Lumbaugh, Fox TV and so on. Marcus explained the tactic of turning anxiety into blind anger: “Anxiety opens you up. Get people angry about something and you can mobilize them. Emotions are reality.”
Marcus makes no predictins, but he does believe that if an election were to be held today, the Democrats would sweep the field. But three years is a long, long time in politics. What if Iraq starts working for Bush? What if the economy just gets better and better?
Marcus has the touch of a natural teacher. He roamed the room and took questions throughout his presentation, while we all ate and drank. To make a point, he grabbed the shoulder of the elderly lady sitting to my left and asked: “Who do ya hate?” She shrieks: “Bush!” Then he asks: “Which Democrat wouldn’t you vote for?” And she screams: “Hillary!” So he asks: “Even if the Republican candidate is Rick Santorum?” And she sputters. She happens to be from Pennsylvania, where liberals are still kicking themselves for not voting for a pro-life Dem and letting Santorum get elected. She turned to me later and said that Hillary used to be a liberal and now she’s nothing but a weathervane. And anyway, a woman couldn’t win the presidency. And she said: “You know what I wish? I wish the Democrats would go back to the old days when they were backing labor and working for the poor.” Then she admitted voting for Nader. I decided she was just not the anxious type. But angry? Oh yes. Very.
And that’s it for now from this coupla Dems abroad.