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ALIMTA (pemetrexed) and Mesothelioma
Lung cancer drug Alimta has fewer side effects
By Tim Friend, USA TODAY
CHICAGO - A new type of chemotherapy for patients with advanced
lung cancer can dramatically enhance quality of life and reduce
debilitating side effects, compared to one of the most commonly
used current treatments, scientists reported Monday.
Experts said that Alimta, a new drug made by Eli Lilly, could potentially
benefit tens of thousands of patients. Alimta is not yet commercially
available.
More than 175,000 patients are diagnosed each year in the USA with
lung cancer. Of those, 85% have non-small cell lung cancer. The
disease in about two-thirds of patients with this kind of cancer
has spread beyond the lungs at the time of diagnosis. The recommended
treatment is chemotherapy, which extends median survival from about
four months with no treatment to about eight months.
The study, presented at a meeting of the American Society of Clinical
Oncology, compared Alimta with Taxotere in a group of 571 patients
at medical centers in the USA, Canada, Spain, Brazil and Italy.
Nasser Hanna of Indiana University in Indianapolis reported that
the side effects were considerably fewer with Alimta.
Survival benefits were about equal, with Alimta patients living
a median of 8.3 months compared with 7.9 months in patients on Taxotere.
For patients with only months to live after their diagnosis, quality
of life becomes a critical issue.
For patients who are diagnosed with non-small cell lung cancer at
earlier stages, the recommended treatment has been removal of the
section of lung containing the tumor. Whether these patients live
longer or better when given chemotherapy after surgery has been
controversial.
But a large international study led by Thierry Le Chevalier of the
Gustave Roussy Institute in Villejuif, France, suggests chemotherapy
may be beneficial. The study of 1,867 patients from 33 countries
found that patients who received surgery plus chemotherapy had about
a 5% survival benefit over a period of five years.
Worldwide, 1.2 million people are diagnosed with lung cancer each
year. About one-third are treated with surgery and may benefit from
adding chemotherapy to their treatment, Le Chevalier said. The benefit
may seem small, but it translates into the prevention of 7,000 deaths
per year worldwide.
Another study, conducted by Roy Patchell of the University of Kentucky
in Lexington, found that patients whose spinal cords have become
compressed by tumors that have spread from other organs can gain
significant relief from a new surgical procedure to remove the tumor.
| Interview
of Doctor Vogelzang |
At the annual meeting of the American Society of Clinical Oncology
the Alimta study was presented. According to the study, many patients
on Alimta lived longer and experienced less pain than those on alternative
cancer treatments. The physician who authored the study was Nicholas
J. Vogelzang, M.D. from the University of Chicago Cancer Research
Center. The study found that Alimta trial was the largest clinical
trial ever conducted in this disease and the 25 to 30 percent improvement
in survival for patients on the combination therapy is the first time
anyone has documented a significant improvement in patients treated
for mesothelioma.
Shortly, thereafter, Dr. Vogelzang gave an Interview to Ms. Berman
of Medscape.
New Directions for the Treatment of Mesothelioma: An Expert Interview
With Nicholas J. Vogelzang, MD
06/09/2003
Introduction
Malignant pleural mesothelioma (MPM) is an aggressive, yet relatively
rare cancer; about 2000 new cases are diagnosed in the United States
each year.[1] Standard treatment is generally not curative, with median
survival for local disease reported as 16 months and median survival
for extensive disease reported as 5 months.[2] Treatment options vary
by extent of disease, but typically consist of surgical resection,
chemotherapy, and/or palliative radiotherapy.[2]
Over the past few years, some progress has been made in the management
of MESOTHELIOMA, as new agents and combinations of agents have demonstrated
improved survival rates.[3] In an attempt to expand upon these improvements
and to identify ever more effective diagnostic and treatment strategies,
3 studies on the management of MESOTHELIOMA were reviewed during an
Oral Presentation Session at the 39th Annual Meeting of the American
Society of Clinical Oncology.[4-6] After the Session concluded, Medscape's
Shira Berman sat with Nicholas J. Vogelzang, MD, Director of the Cancer
Research Center at the University of Chicago, to discuss the findings
presented and to review their significance in the treatment of the
disease.
Intracavitary Hyperthermic Cisplatin
The first study in the Session, presented by Dr. David Sugarbaker
of Brigham and Women's Hospital in Boston, Massachusetts,[1] evaluated
the use of an intracavitary lavage consisting of hyperthermic cisplatin
followed by intravenous thiosulfate in patients who had undergone
pleurectomy, but who were not candidates for extrapleural pneumonectomy.
The average age of the 44 patients evaluated in the phase 1/2 study
was 70 years, and 88% were older than age 65.
Three dose levels of cisplatin were used: The lowest dose level was
50-100 mg/m2; the intermediate dose level was 175-200 mg/m2; and the
maximum tolerated dose (MTD) was 225 mg/m2. Across all dose levels,
the median overall survival (OS) was 10.5 months, or 13 months among
those who survived surgery; when divided by tumor type, patients with
epithelioid disease fared better than did those with mixed or sarcomatous
disease.
The median OS seen with the lowest doses was 6 months, and the recurrence-free
survival (RFS) was 3.6 months; at the intermediate dose level, the
median OS was 11 months and the RFS was 7.6 months; at the MTD, the
median OS was 22 months and the RFS was 20 months. Dose level of cisplatin
was an independent predictor of survival, and each successive lower
dose level conferred a 22% greater risk of death on the patient. Although
23 patients treated with the MTD showed no grade 3/4 toxicities, the
rate of atrial fibrillation (AF) was 32%, and the rate of deep venous
thrombosis was 11%.
Medscape: What did you see as the key findings in this study?
Dr. Vogelzang: This feasibility study was clouded by 3 things.
One, it's highly technical and therefore difficult to export. It will
probably be replicated in several technical centers around the country,
but I think it's unlikely to be used outside of those settings. Two,
the side effects that were seen may be directly related to the high
temperature and the high dose of chemotherapy, although we weren't
given a lot of data on the evolution of the regimen. When I asked
[Dr. Sugarbaker] what his plans were beyond this hypothesis-generating
phase 1/2 study, he didn't answer directly. I suspect they're pausing
before continuing this.
The third issue is that the median survival is not that good. A cluster
of mesothelioma mavens gathered after the sessions, and we all agreed
that we could reach this survival rate with regular chemotherapy.
I suspect they'll extend it to the extrapleural pneumonectomy patient
population because it offers a fully empty cavity, and very few people
do just a decortication and pleurectomy; it's not a commonly done
procedure.
Medscape: So given the limited application, what does a study such
as this add to the overall body of knowledge on mesothelioma?
Dr. Vogelzang: It's not a blind alley, but a very steep canyon
that very few people would try to cross. It's highly appropriate for
this kind of research to go on; it's very creative. But it will require
a consensus that this is the path to take. There will be a few brave
souls who will try this canyon up over the mountains, but I think
that this is not the way to go. It requires a very skilled surgeon;
in truth, this can probably be done only by a handful of surgeons
across the country. And when the skill level is that high, it just
isn't translatable.
Predicting Survival With FDG-PET
The second study in the Session, presented by Dr. Raja M. Flores of
Memorial Sloan-Kettering Cancer Center in New York, NY,[2] evaluated
the feasibility of using the FDG-PET standardized uptake value (SUV)
to predict survival. Of the 65 patients evaluated, 54 were men and
11 were women; the median age was 65 years. The median SUV in the
46 patients with epithelioid disease was 6.5; the median SUV in patients
with mixed disease was 6.8; and the median SUV of patients with sarcomatous
disease was 3.8.
A nearly perfect inverse relationship was seen between SUV and survival,
such that a greater SUV correlated with a shorter survival. The median
survival in patients with an SUV < 4 was 24 months vs a median
survival of 14 months in patients with an SUV > 4, demonstrating
a 3.3% greater risk of death with the higher SUV. When evaluated by
tumor type, 80% of patients with epithelioid disease and low SUV were
alive after 36 months vs 0% of patients with mixed or sarcomatous
disease and a high SUV after only 18 months. In the highest-risk group,
there was a 3.2% greater risk of death with the combination of a high
SUV and mixed or sarcomatous disease. Stage of disease did not independently
predict survival in these patients.
Medscape: What did you see as the key findings in this study?
Dr. Vogelzang: The results were relatively modest, although
the approach was correct -- trying to understand the biology beneath
the disease. The best biologic study is the microarray, or other similar
mechanism, so perhaps this is molecular biology at the visual limit
edge. We know that some cancers are very hot and that some are very
cold. What [Dr. Flores] showed is that those cancers that are hot
-- with a higher SUV -- are "bad," and those that are cold
-- with a lower SUV -- are "good." This suggests that the
growth rate of the cancer is somehow related to outcome. I think it's
real, I think it's biologic, and I think it's a very nice step forward.
The problem is that Medicare won't pay for PET scans, and they're
expensive, so it might not be practical to implement. However, the
PET scan would be perfect for a clinical trial setting -- if people
can arrange for a PET scan to be done before and after chemotherapy,
I think it would be a very nice addition. You can't do biopsies on
everyone, but if the PET scan correlates with the molecular biology,
then this could be a useful tool.
Effect of Chemotherapy on Quality-of-Life Parameters
The third study in the Session, presented by Dr. Richard Gralla
of Columbia-Presbyterian Medical Center in New York, NY,[3] evaluated
the impact of pemetrexed plus cisplatin on quality-of-life (QOL)
parameters defined by the validated LCSS-meso tool. The median age
of the patients enrolled in the phase 3 trial of the combination
vs cisplatin alone[7] was 60 years, and most patients had stage
III or stage IV disease.
At the start of the trial, the median score recorded by the patients
on a visual analog scale was in the third quartile, indicating moderate
severity. In addition, 3 or more symptoms were noted on presentation.
Over the course of the trial, evaluations were collected weekly
in all participating centers; initial and follow-up data were available
for 96% of patients. Differences in QOL parameters began at 6-9
weeks with the combination, despite no improvements in survival
data at this point. After 18 weeks of therapy, at which point survival
was significantly improved vs cisplatin alone, significant improvements
were seen with the combination in all thoracic parameters, as well
as in fatigue, anorexia, and level of activity. These improvements
were also significant in the summary evaluation completed by the
patients at trial completion.
Medscape: What did you see as the key findings in this study?
Dr. Vogelzang: First, 93% of these patients are symptomatic.
That's a very high percentage; I didn't expect it to be that high.
So the patients are telling us that they're sick, and we're no longer
able to say that our patients have a performance status (PS) of
0. Technically, they're PS 0, but they're telling us that there's
still something wrong. Second, there was an extremely high questionnaire
completion rate, which makes this a very powerful study.
Third, the symptoms of pain, dyspnea, and cough were significantly
improved even before the general symptoms of fatigue, anorexia,
and activity, indicating that their symptoms are referable to the
local cancer, and are not necessarily due to the cancer spread throughout
the body. Also, it's interesting to note that an improvement in
the global measure of QOL was present at 12 weeks and was significant
by 18 weeks, suggesting that the improvement is, although not abrupt,
certainly modest.
The one thing we don't yet know is if QOL predicts survival -- if
people who have a higher QOL also have a longer survival. Also,
it isn't clear if cough and shortness of breath improve before pain
or if they're all getting better at around the same time. It may
be a general trend, so by the time you measure each parameter, they've
become generally better; the symptoms are all probably correlated
with anticancer activity in general.
Medscape: How would you translate these data for the average
patient?
Dr. Vogelzang: I think the biggest issue is that patients
don't have to fear the chemotherapy. And if they're getting this
combination, they're almost certainly going to feel better -- even
the nonresponders, even the progressors, even those who have drug
toxicity feel better. So you can honestly say to the patient: Even
if your tumor doesn't shrink, you're going to have some improvement
in your symptoms. That's not bad at all.
From a QOL perspective, when you compare the intensity of a pleurectomy
with chemotherapy, I think patients are going to choose chemotherapy
over surgery. Chemotherapy offers a more global improvement, whereas
surgery may be helpful in only a selected population. Ultimately,
chemotherapy offers something for everyone; surgery offers a lot
for a small number of patients.
Summary
Medscape: Putting all of this together, where do we go from here?
Dr. Vogelzang: Based on the data from these studies and from
what was presented in the poster sessions, we've learned a number
of things. Chemotherapy now has an established role in the treatment
of mesothelioma. Almost everyone, even if they're surgical candidates,
should get chemotherapy. Also, giving chemotherapy in the second
line is valuable and needs to be tested in a prospective trial setting.
Although we all thought that chemotherapy helps, we now see that
it's like breast cancer -- if you give a second round after the
first one doesn't work, you still get a benefit.[8] That's pretty
remarkable.
Finally, we have to focus more on the molecular biology of the disease
to learn who's going to improve most on the different treatments.
We're pretty good at predicting who's going to do poorly -- we just
have to work more on predicting who's going to do well.
Alimta Clinical Trials
Trial I.
Title: ALIMTA (pemetrexed) alone or in Combination with Cisplatin
for Patients with Malignant Mesothelioma. Reference # 6093.
Location: This is an expanded access "Protocol for Treatment"
open to physicians throughout the United States.
Protocols: The purpose of this protocol is to extend the
clinical experience with ALIMTA plus cisplatin in patients with
malignant pleural mesothelioma and to collect additional safety
information in this patient population.
Inclusion Criteria:
- have a proven diagnosis
of malignant mesothelioma in patients not candidates for
curative surgery
- prior chemotherapy for your disease is allowed
- measurable lesion is not required
- have an adequate performance status
- sign an informed consent form
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Exclusion Criteria:
- You are excluded from
this trial if you have received any investigational agent
within 4 weeks before enrolling in this study
- You are excluded from this trial if you have
received radiation within the previous 2 weeks
- You are excluded from this trial if you are
a candidates for curative surgery
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Please note that more specific inclusion/exclusion criteria must
be met prior to entering the trial.
Trial II.
Title: ALIMTA Plus Gemcitabine (Gemzar) for Patients with
Malignant Pleural or Peritoneal Mesothelioma who have not had previous
chemotherapy. Reference # 7214.
Location: Aurora, Colorado; Chicago, Illinois; Tampa, Florida;
Baltimore, Maryland; Boston, Massachusetts; Albuquerque, New Mexico;
New York, New York; Madison, Wisconsin.
Protocol: The purposes of this study are to determine -
- The safety of ALIMTA plus
Gemcitabine (Gemzar) and any side effects that might be
associated with the combination of these two drugs.
- Whether ALIMTA plus Gemcitabine (Gemzar)
can help patients with mesothelioma live longer.
- Whether ALIMTA plus Gemcitabine (Gemzar)
can make the tumor smaller or disappear, and for how long.
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To see if patients feel better while taking ALIMTA plus Gemcitabine
(Gemzar).
Inclusion Criteria:
- Diagnosis of mesothelioma that can be treated
with chemotherapy
- Have received no prior chemotherapy for mesothelioma
- Have at least one measurable lesion
- Have an adequate performance status
- Have signed an informed consent
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Exclusion Criteria:
- Previous treatment with chemotherapy for
mesothelioma
- Treatment with an investigational drug within
the last 30 days, previously completed or withdrawn from
this study or any other study investigating ALIMTA
- Treatment with radiation therapy within the
last 4 weeks
- Brain metastasis that is uncontrolled
- Active infection or other serious condition
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Please note that more specific inclusion/exclusion criteria must
be met prior to entering the trial.
To learn more about new mesothelioma medications and clinical
trials call for a free information package 1-800-362-1479
or email us below.
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