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| Tracks 1-23 | ||||||||||||||||||||||||||||||||||||||||||||||||
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Select Excerpts from the Interview with Dr Vogel and His Patients
Track 2: Case 1
DR VOGEL: Ms C is a practicing attorney who was originally diagnosed in March 2001 at the age of 55. She presented with a 12-cm mass, which was
found to be an ER-positive, PR-positive, HER2-negative, invasive lobular
carcinoma. She underwent a mastectomy, and six out of 20 nodes were
positive.
She received four cycles of AC and four cycles of docetaxel followed by radiation therapy to the chest wall and draining lymphatics, and then she began tamoxifen. She did well, but only for about a year, when she was diagnosed with a new primary in the contralateral breast. Tamoxifen was discontinued, and she underwent a left mastectomy.
Again it was an ER-positive, PR-positive, HER2-negative, infiltrating lobular carcinoma, but this time the nodes were negative. She did not receive radiation or chemotherapy.
She began an aromatase inhibitor, but she was unable to tolerate either anastrozole or letrozole because of unbearable arthralgias. She took exemestane for two years, but disease progression was found in the liver in November 2004.
She then received fulvestrant and did not respond. Then she was treated with high-dose estrogen in March 2005. We used estradiol at 30 mg/day, which is supplied as 2-mg tablets, so she took five tablets three times a day.
Much to everyone’s delight, she experienced very little toxicity and a complete response in the biopsy-proven liver metastases. She continues on estradiol and has now been on it for a year.
Comment from the patient
PATIENT: I have an excellent quality of life. I try to travel about every six weeks for four or five days. I have eliminated as much stress as possible from my life, because I believe stress can trigger cancer. I try not to get aggravated in my work. It just isn’t worth it.
Of course, you have a whole different life perspective after all this. Each day is wonderful, and you don’t sweat the small stuff. I practice family law, and often my clients call frantically. Whereas I used to get really upset, I don’t now. What seemed to be major crises are no longer crises. I tell my clients, “This will pass. A year from now, you won’t remember any of this.” I recommend counseling to everybody.
I use complementary medicine, and I do meditation, hypnosis — whatever it takes. I read spiritual books and try to stay out of the fear in my mental framework. You have to stay out of the fear. The anxiety and fear can be overwhelming, and that’s no way to live.
DR LOVE: That’s an unusual
choice of therapy.
DR VOGEL: Well, it’s not an
unusual choice of therapy
for me or for many of the
“hormonalists.”
As you recall, in the past, diethylstilbestrol, which is now off the market, was the only available hormonal preparation until tamoxifen became available. We participated in the original tamoxifen trials in the early 1970s. At that time, one of the original trials compared DES to tamoxifen (Ingle 1981; [3.1]).
As a little history, the estrogens did every bit as well as tamoxifen, but some people couldn’t tolerate estrogens. One of the problems was nausea and vomiting, and some had intractable nausea and vomiting. Some developed menstrual-like cramps, which can be troubling. Some of the women we treated with high-dose estrogen mentioned an increase in libido, which they found to be a positive side effect.
This case illustrates that we almost never run out of hormone options. For a woman with a hormone-sensitive cancer, you can always rechallenge with tamoxifen or other aromatase inhibitors at some point in the very protracted course that many of these women experience.
Metastatic breast cancer can be a chronic disease, and therefore the use of high-dose estrogen shouldn’t be forgotten as a therapeutic maneuver.
Track 4: Case 2
DR VOGEL: The next three cases relate to the use of capecitabine in metastatic
disease. Along the way, we adopted a blanket policy in my practice of treating
patients with a total dose (not mg/m2) of 2 g/day of capecitabine 14 days on,
seven off.
In an occasional overweight individual, we might go up to 2,500 mg as a starting total dose. Even at these doses, very frequently we’re forced to cut back. However, the beautiful responses you can see with relatively modest doses of capecitabine like these are incredible.
The first patient was diagnosed in 1994, at the age of 67, with a four-centimeter, ER-positive, PR-positive, node-negative invasive lobular carcinoma. She was treated at another institution with a right partial mastectomy and sentinel node dissection, followed by radiation therapy and tamoxifen.
Tamoxifen was stopped after four months because of elevated liver function test results. At that time, not many other hormones were available, so she was just followed. She did really well until seven years later, when she developed a new primary tumor in the ipsilateral breast, which proved to be an infiltrating ductal carcinoma.
Comment from the patient
DR LOVE: What’s your life like nowadays?
PATIENT: Boring! I meet friends for lunch sometimes, or sit at home. I love music. I’m a singer. I sing opera, or I did. I would love to sing again, but I don’t know where to throw my voice.
DR LOVE: What’s this experience been like overall for the last 12 years?
PATIENT: I’ve handled it extremely well. I have a positive attitude, and that helps. I never really worry. I’m not even worried now after having it come back five times. What will be will be, and lately I’ve been saying that this should be the worst thing that happens because I feel fine, I really do. I feel very good.
Shortly thereafter she developed local skin lesions that were surgically excised and treated with radiation therapy. No additional therapy was administered. In 2002, she had another skin recurrence and began taking letrozole. She had a good response that lasted about 1.5 years. Then fulvestrant was initiated, but it was stopped after three months because of disease progression.
By this time, she had a couple hundred small erythematous nodules on the right chest wall. At another institution, she was treated with reduced doses of capecitabine, but the dose was not as low as we generally use. I venture to say that she received something like 3 gm/day.
It certainly was not wrong to dose capecitabine this way, given common practice, but it backfired on her. She ended up in the hospital with severe stomatitis, diarrhea and horrible hand-foot syndrome. Because of that experience, she sought another opinion and was adamantly opposed to the reintroduction of capecitabine.
We treated her with high-dose estrogen. However, unlike the first patient, the tumors continued to progress unabated. I finally convinced her in December 2004 to resume capecitabine but at a total dose of 2 g/day, two weeks on and one week off. Interestingly enough, this patient — with these 200 lesions on the chest wall — had a complete response, and she continues on capecitabine to this day.
DR LOVE: Has she had any side effects or toxicity?
DR VOGEL: Very little. She complains of some fatigue, but she’s an active
woman and has done beautifully.
Track 6: Case 3
DR VOGEL: This woman was diagnosed with an infiltrating lobular carcinoma
in 1995 at the age of 61. She had five positive nodes, and her tumor was ER-positive,
PR-positive and HER2-negative. She underwent a left mastectomy,
adjuvant AC followed by radiation therapy to the chest wall and supraclavicular
area, and five years of tamoxifen.
In 2003 she had a regional recurrence in the previously irradiated left supraclavicular area and started to develop a brachial plexopathy. She was in a lot of pain, and we entered her into a local clinical trial studying the combination of docetaxel and capecitabine. It started out as a Phase II study, and it turned into a reverse Phase I study as we kept reducing the dose in subsequent cohorts of patients.
Comment from the patient
PATIENT: My arm was hurting very badly when I started the Xeloda®, but the pain went away and the lump disappeared. I returned to my usual activities. I’m very busy in my church. I have a musical I am working on. I don’t have time to really think about myself, and I don’t want to. I have so much energy and I am so thankful. I have four grand children and three daughters, and we’re always doing something together.
DR LOVE: How has it been receiving capecitabine compared to the other chemotherapy?
PATIENT: It’s better. I’m not losing my hair, my nails or anything. When you’re getting intravenous chemotherapy, it makes you sick. I was sick all the time with it, but taking the pills — I take two in the morning and two in the evening for a two-week period — is easy. It’s not making me sick, and my energy level is very high. I feel healthy.
We started docetaxel at 36 mg/m2 on days one and eight and capecitabine at 1,500 mg twice a day, which is a relatively typical dose but lower than the package insert dose. She experienced a lot of side effects — stomatitis, hand-foot syndrome and diarrhea — so the dose was reduced, and she did very well. Her neuropathy improved, her brachial plexopathy cleared and within a few months she had no palpable supraclavicular adenopathy. She had a beautiful response to the reduced doses of docetaxel and capecitabine.
In July 2003, she took a chemotherapy break and began letrozole. She stayed on that for approximately 1.5 years, when she discontinued the drug on her own. Why she did that remains a matter of conjecture. Within two months, her disease recurred and letrozole was restarted. She stayed on it for about six months, and by that time she had developed a new lesion in a very strange place — a painful 2.5-cm mass within the left biceps. She was also experiencing recurrent symptoms of her brachial plexopathy.
She was entered into the EFECT trial, which randomly assigned patients to receive either fulvestrant or exemestane (3.2). She experienced progression on whichever medication she was assigned, and we started her on capecitabine at our standard total dose of 2 g/day. At the same time, we referred her to a surgeon to see if he could remove this mass, which had now grown to about four centimeters. He didn’t want to attempt it, so we referred her for radiation therapy.
When she came back to see me, I commented that the radiation was doing great, and she replied, “I never went for radiation because the tumor started to shrink and nothing was left.”
She continues to receive capecitabine, with complete relief of all symptoms and complete disappearance of the mass. She had a dramatic response within a month and remains on capecitabine eight months later with continued response.
Track 10: Case 4
DR VOGEL: The next patient was 29 years old when she was first diagnosed in
1994, and she received adjuvant CMF. She later presented with a local regional
recurrence; it was during the era of high-dose chemotherapy and stem cell
transplant. She was a proactive person, and although I was never a proponent
of this approach, she fell into the category of patients — Stage IV, NED — for
which, at the time, I felt if
any group of patients might
benefit from that approach,
we should try it.
Comment from the patient
DR LOVE: How would you compare your quality of life on Xeloda versus some of the other chemotherapies you’ve received?
PATIENT: It’s a breeze — there is no comparison. Xeloda means staying home, taking your own medicine orally versus sitting in a chair for hours, being pricked with needles, and getting that nauseous feeling during which you have to keep eating to get that taste out of your mouth and eliminate the nausea.
I think the main thing, as a woman, is not losing my hair. I know it sounds weird, but if I had hair going through chemotherapy, I could have dealt with it better. Not having any hair made going through chemotherapy harder.
When you see someone and they don’t have hair, you know they’re sick. When you see someone with hair, you don’t make that connection. My kids were young when I went through chemotherapy, and they knew I was sick when I had no hair. When I had hair on capecitabine, I was still sick, but they were less aware of it.
She received high-dose chemotherapy and a stem cell transplant on a Duke University protocol. She also received thalidomide on protocol, and then maintenance tamoxifen. In June 2002 she developed a mass in the right side of her neck, and her CEA increased into the many hundreds. She tried different hormonal therapies, including letrozole and fulvestrant.
Then she was treated on the local clinical trial studying docetaxel and capecitabine. She received tolerable doses of these medications — docetaxel at 30 mg/m2 and capecitabine at 1 gm twice a day for 14 days — and didn’t have much of a problem. Her supraclavicular nodes disappeared, and her CEA decreased from 272 ng/mL to 82 ng/mL.
However, in October 2004 she developed right cervical and mediastinal adenopathy. We tried radiation therapy to eradicate those foci of disease, but then she developed another metastasis in the left posterior neck — a very strange presentation. It was actually a subcutaneous lesion that measured about two centimeters. It was surgically removed, and she was treated with capecitabine.
Now in a Stage IV, NED situation, her tumor markers have continued to regress on capecitabine at 2 g/day as the total dose. She has been receiving this for about eight months while leading a normal life with no manifestations of recurrent disease.
Tracks 14-15: Case 5
DR VOGEL: The next two patients have HER2-positive disease. The first
woman was diagnosed at the age of 39 with infiltrating lobular carcinoma of
the breast. She is a very outgoing, bouncy, outspoken and assertive woman.
When she was diagnosed in 1998, she had no question in her mind that both
breasts were going to be removed. She underwent bilateral mastectomy, and
the main mass was 3.8 centimeters.
Fifteen out of 19 nodes were positive, and the tumor was reported to be ER-negative and PR-negative, which is an interesting point I’ll discuss later. The tumor was also HER2-positive, and this was prior to the commercial availability of trastuzumab.
She was treated with doxorubicin and cyclophosphamide almost immediately after surgery. A metastatic workup was done at another institution, and she was found to have tumor in the wall of the surgical defect and bone metastases. For whatever reason, and I can’t reconstruct it because she was not my patient at that time, she was taken off doxorubicin and cyclophosphamide and switched to paclitaxel.
She then heard about the compassionate use of trastuzumab and entered the lottery. As you recall, prior to the commercial availability of trastuzumab, a lottery was held, and she was selected to receive it. We elected to treat her with induction chemotherapy with a rather heretical regimen at that time, which was capecitabine and trastuzumab.
DR LOVE: What was your reason for selecting capecitabine?
DR VOGEL: It was felt that the patient’s disease had progressed on paclitaxel,
doxorubicin and cyclophosphamide, and capecitabine was approved for that
particular subpopulation of patients.
Convention at that time indicated, based on Mark Pegram’s in vitro data, that 5-fluorouracil and capecitabine were not synergistic with trastuzumab, unlike many other agents, which were felt to be synergistic or additive. However, we elected to “fly in the face of convention” and treated her with our standard capecitabine dose of 2 g/day and standard doses of trastuzumab. She responded beautifully.
Comment from the patient
PATIENT: Herceptin® is easy to tolerate. It has very few side effects. I look at it as what I have to do to stay alive, and I was willing to do anything to stay alive. So I consider the weekly visit to the doctor as my job. It’s what I do every week.
DR LOVE: What was your experience with capecitabine?
PATIENT: I rarely had any side effects on capecitabine. It was a pill, and I took a couple in the morning and a couple at night, two weeks on and one week off. I had a little reddening of my hands and feet but no real side effects from capecitabine.
DR LOVE: What’s it been like to go through this experience?
PATIENT: You look at things differently. When people say, “Don’t sweat the small stuff, and everything is small,” they mean it. I remember the first time going into an MRI. I thought, “Ugh, I can’t breathe.” Now it’s not a big deal to me. When people complain, “Oh, I have to go into this tube,” I say, “You’ve got to be kidding! The only time I get any rest is when I’m lying in the tube.”
When people say, “You have your health, you have everything,” they’re right. So I enjoy every day. I do what I want. I try to have fun in everything I do. I really don’t sweat the small stuff because when somebody tells you that you have cancer, your whole life changes in a second.
The disease was largely in the bone, so it was difficult to follow. The lesions in the bone stabilized. Being an assertive and sometimes aggressive patient, she elected to stay on capecitabine for a year and a half. I probably would have taken her off capecitabine at about six months and tried to maintain her on trastuzumab alone.
She’s now been on single-agent trastuzumab for more than six years. She has inter-current problems with lymphedema, but otherwise she has been leading a normal life. She comes in for zoledronic acid and trastuzumab. We’ve offered her every two-week and every three-week dosing, but for the most part she comes in weekly.
As an aside in this case, one day we were discussing with the patient the problem of quality control with the testing for HER2, ER and PR. She said, “You know, I was estrogen and progesterone receptor-negative.”
I told her we had our own series running with Craig Allred, who found that 30 percent of our 30 tumor specimens originally reported as ER-negative and PR-negative were positive.
Even though we didn’t intend to do anything with the information, she insisted that we send off her tumor blocks. Indeed, her tumor was found to be ER-positive and PR-positive.
Fortunately, at this juncture, we haven’t had to use that information. Her disease continues to be controlled by trastuzumab, and she doesn’t want to stop this agent. I also see no reason to add the additional toxicities from an aromatase inhibitor.
DR LOVE: I find the percentage of false negatives in ER testing to be very
disturbing.
DR VOGEL: It really is, and the American College of Pathologists needs to
do something about it. They’re the only body that can do anything. I know
the NCCN and ASCO are both starting to exert major pressure in this area. I
participated in a guidelines development meeting for NCCN recently at which
the issue of quality control for HER2 monitoring was discussed. I’m sure a
guideline will be forthcoming shortly.
DR LOVE: Do you see a light at the end of the tunnel for HER2 and ER testing?
DR VOGEL: I don’t see a light at the end of the tunnel. I’m rather pessimistic,
unless the American College of Pathologists pulls together all of its resources.
They were able to do that once before, when Jim Wittliff sent powders to labs
to test for estrogen and progesterone receptors using dextran-coated charcoal.
That converted a major quality control issue into a minor quality control issue back in the 1970s and early 1980s. We as medical oncologists face, on a daily basis, the problem of sending out tissues to referee pathologists just because we can’t trust our laboratories.
Track 21: Case 6
Comment from the patient
PATIENT: My reaction to breast cancer was that I had to fight, and I cannot give up. The theme in our house is “never give up.” No matter how mad or how sad we are, we never give up. I was able to overcome the year I had with the chemotherapy with three little girls. I had to fight for them. I love my husband and my kids, but my girls are my main focus in continuing my life.
It has been like a roller coaster with ups and downs, but I thank God a lot. We’re very strong believers in our house, but it’s not easy. I’m the one who is always telling everybody to have faith and be strong, but sometimes I need that too. This time around has not been easy for the whole family. The girls are older, and it is more difficult for them to accept that Mom is sick. It’s hard for them to help me because they always have had all the help in the house.
It has not been easy for my husband, either. Sometimes I want to always be the strong one in the house. If I’m not strong, then they get hesitant or aggravated or sad because they don’t see the strong woman that they’re used to seeing. But sometimes it’s not easy.
DR VOGEL: This 42-year-old
woman was diagnosed
in 1995, at the age of 31,
with an infiltrating ductal
carcinoma. She had bilateral
mastectomies with reconstruction.
Within a year, she
was diagnosed with bone
metastases, and her tumor
was 3+ positive for HER2.
She was eligible for and
joined the pivotal trastuzumab
clinical trial. Because
she had received doxorubicin
in the adjuvant setting, she
was randomly assigned to
paclitaxel and trastuzumab
(Slamon 2001; [3.3]).
After a period of time, she received single-agent trastuzumab for approximately a year, and then she developed progression in the bone. She went on the extension trial, on which we were allowed to continue trastuzumab and added cisplatin. In spite of that, her disease progressed rapidly in the bone. Then she had a good response to trastuzumab and vinorelbine; however, after a year, she experienced progression. The big problem was a skull metastasis.
In January 1998 her ovaries were removed as a therapeutic maneuver and trastuzumab was continued. In spite of that, the skull metastasis continued to increase in size, and we radiated her skull. We then added toremifene, and she remained on toremifene and trastuzumab for 6.5 years.
In February 2005 she developed further progression in the bone and was changed to letrozole with trastuzumab for a year. She then developed a new lesion in the left femur and was put on fulvestrant with trastuzumab. She also underwent radiation to the left femur, which is her only symptomatic lesion.
This young woman, the mother of three young girls, never dreamed she would be able to see her little one driving a car. Her firstborn is now 17 years old, driving a car, and doing beautifully in school. The patient has been on trastuzumab now for a total of 10 years.
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