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Reviews
on Recent Clinical Trials
ISSN: 1574-8871
Reviews on Recent Clinical Trials
Volume 1, Number 1, January 2006
Contents
Epidermal Growth Factor Receptor (EGFR) Targeted Therapies
in Non-Small Cell Lung Cancer (NSCLC) Pp. 1-13
Giulio Metro, Giovanna Finocchiaro, Luca Toschi, Stefania
Bartolini, Elisabetta Magrini, Alessandra Cancellieri, Rocco
Trisolini, Luciano Castaldini, Giovanni Tallini, Lucio Crino
and Federico Cappuzzo
[Abstract]
[Full Text Article]
Recent Clinical Trials of Cladribine in Hematological
Malignancies and Autoimmune Disorders Pp. 15-34
Tadeusz Robak, Agnieszka Wierzbowska and Ewa Robak
[Abstract]
[Full Text Article]
Medical Treatment of Gastrointestinal Stromal
Tumors: State of the Art and Future Perspectives
Pp. 35-42
Gaetano Apice, Amalia Milano, Giovanni Salvatore Bruni,
Rosario Vincenzo Iaffaioli and Francesco Caponigro
[Abstract]
[Full Text Article]
Combined Modality Treatment of Glioblastoma Multiforme:
The Role of Temozolomide Pp. 43-51
Carsten Nieder, Markus Adam and Anca L. Grosu
[Abstract]
[Full Text Article]
Topical Therapy for Actinic Keratoses: Current
and Evolving Therapies Pp. 53-60
Jeffrey M. Weinberg
[Abstract]
[Full Text Article]
The Development of Future Research Strategies
from Reviewing Antiemetic Trials for Chemotherapy Induced
Emesis Pp. 61-66
Ian N. Olver
[Abstract]
[Full Text Article]
Clinical Benefit of Idiotype Vaccines: Too Many
Trials for a Clever Demonstration? Pp. 67-74
Maurizio Bendandi
[Abstract]
[Full Text Article]
Functional Recovery After Stroke: A Review of
Current Developments in Stroke Rehabilitation Research
Pp. 75-80
Boudewijn Kollen, Gert Kwakkel and Eline Lindeman
[Abstract]
[Full Text Article]
A Review of Methods for Ensuring the Comparability
of Comparison Groups in Randomized Clinical Trials Pp.
81-86
Vance W. Berger
[Abstract]
[Full Text Article]
Abstracts
[Back to top]
Epidermal Growth Factor Receptor (EGFR) Targeted Therapies
in Non-Small Cell Lung Cancer (NSCLC)
Giulio Metro, Giovanna Finocchiaro, Luca Toschi, Stefania
Bartolini, Elisabetta Magrini, Alessandra Cancellieri, Rocco
Trisolini, Luciano Castaldini, Giovanni Tallini, Lucio Crino
and Federico Cappuzzo
[Full Text Article]
The Epidermal Growth Factor Receptor (EGFR) family, including
EGFR, HER2, HER3, and HER4, is implicated in the development
and progression of cancer, and is expressed in many human
epithelial malignancies, including Non-Small Cell Lung Cancer
(NSCLC). Several molecules were synthesized to inhibit the
extracellular domain of EGFR, such as cetuximab (Erbitux),
the extracellular domain of HER2, such as trastuzumab (Herceptin)
or the EGFR tyrosine kinase domain, such as gefitinib (Iressa)
and erlotinib (Tarceva). Gefitinib and erlotinib are orally
active, selective EGFR tyrosine-kinase inhibitors (EGFR-TKI)
that produce objective response rates in about 10% of advanced
NSCLC. More recently, erlotinib produced a significant improvement
in survival when compared to placebo in pretreated NSCLCs.
Among clinical characteristics, although female gender, and
adenocarcinoma histology, showed to be significantly associated
to TKI sensitivity, never smoking history is probably the
most relevant factor. Presence of specific EGFR gene mutations
or EGFR gene amplification confer a particularly sensitive
phenotype, and patients with activation of the anti-apoptotic
protein Akt are more sensitive, when Akt activation is sustained
by a EGFR dependent mechanism. Cetuximab is a human-murine
chimeric anti-EGFR IgG monoclonal antibody that has demonstrated
both in vitro and in vivo antitumor activity
in tumor cell lines expressing EGFR. It has shown impressive
activity when combined with radiation by increasing the antitumor
effect of radiation therapy. Cetuximab has a synergistic effect
with cisplatin and may play a role in reversing resistance
to chemotherapy. Cetuximab demonstrated to be active in pretreated
NSCLCs, and its activity as first-line therapy in combination
with chemotherapy is currently under evaluation. Efforts should
be made for the identification of biological mechanism underlying
cetuximab sensitivity and emerging data suggest that the drugs
is more active in patients with EGFR gene amplification. In
NSCLC, trastuzumab produced disappointing results when combined
with chemotherapy, but probably patients were not properly
selected. Recent findings in gefitinib treated patients support
HER2 analysis by fluorescence in situ hybridization as a complementary
test for selection of patient candidate for EGFR targeted
therapies. Combination of EGFR targeting agents with other
biological drugs is under investigation.
[Back to top]
Recent Clinical Trials of Cladribine in Hematological Malignancies
and Autoimmune Disorders
Tadeusz Robak, Agnieszka Wierzbowska and Ewa Robak
[Full Text Article]
The purine nucleoside analog – cladribine (2-chlorodeoxyadenosine,
2-CdA) is a cytotoxic agent with high activity in lymphoid
and myeloid malignancies. It is also an effective drug in
some autoimmune disorders. 2-CdA is usually administered intravenously
in continuous or 2-hour infusion. Recently however, new formulation
of this agent has been developed for subcutaneous and oral
administration. 2-CdA is widely established as first line
standard treatment for hairy cell leukemia. Moreover several
clinical trials have demonstrated that this agent, used alone
or in combination with other cytotoxic drugs, showed good
efficacy and acceptable toxicity profile in the treatment
of chronic lymphocytic leukemia, Waldenström macroglobulinemia,
low-grade non-Hodgkin’s lymphoma and acute myeloid leukemia.
Moreover, some studies indicate that 2-CdA has some activity
in progressive multiple sclerosis and other autoimmune disorders
including autoimmune hemolytic anemia, rheumatoid arthritis,
systemic lupus erythematosus, psoriasis and in patients with
refractory factor VIII inhibitors. This review article will
summarize the results of recent clinical trials with 2-CdA
in hematological malignancies, multiple sclerosis and other
autoimmune diseases.
[Back to top]
Medical Treatment of Gastrointestinal Stromal Tumors: State
of the Art and Future Perspectives
Gaetano Apice, Amalia Milano, Giovanni Salvatore Bruni,
Rosario Vincenzo Iaffaioli and Francesco Caponigro
[Full Text Article]
Gastrointestinal Stromal Tumor (GIST) is the most common
mesenchymal neoplasm of the gastrointestinal tract, and it
is characterized by the occurrence, in > 90 % of cases,
of a gain of function mutation in the c-kit proto-oncogene.
STI-571 (imatinib mesylate), a selective KIT tyrosine kinase
inhibitor, has changed the natural history of this disease,
since it has shown high effectiveness in metastatic GIST,
and it is currently under investigation also in the adjuvant
and neoadjuvant setting. Mechanisms of resistance to imatinib
mesylate include both de novo, and, more frequently,
acquired resistance, which may occur after several months
of drug administration and possibly depends, in most cases,
upon an acquired second mutation. In order to overcome imatinib
mesylate resistance, the addition of other drugs may be considered
in patients who have less than an optimal response to imatinib
mesylate monotherapy. Investigational agents that are being
studied in this setting include the mammalian target of rapamycin
(mTOR) inhibitor RAD 001 and the protein kinase C inhibitor
PKC412. In addition, other KIT tyrosine kinase inhibitors
with anti–VEGF receptor inhibitory activity, such as
SU11248, PTK787/ZK787 and AMG 706, are currently being explored
as second line monotherapy for imatinib mesylate–resistant
GIST. Finally, another new drug, ecteinascidin (ET-743), that
blocks cell cycle progression in G2/M phase through a p53–independent
apoptotic mechanism, has shown important preclinical and clinical
activity against a number of human solid tumors, including
GIST.
[Back to top]
Combined Modality Treatment of Glioblastoma Multiforme:
The Role of Temozolomide
Carsten Nieder, Markus Adam and Anca L. Grosu
[Full Text Article]
Despite of improvements in the biological and molecular characterization
of glioblastoma multiforme and studies of factors associated
with tumor growth and progression, this type of malignant
astroglial brain tumor is still difficult to treat. The present
article reviews established and emerging prognostic and predictive
factors and their potential influence on future therapeutic
efforts. Recent developments in standard treatment options
(surgery, radiotherapy and chemotherapy) are summarized. The
integration of the oral cytotoxic agent temozolomide into
current treatment protocols of postoperative combination therapy
with radiation and drugs is discussed, especially in the context
of the recently published randomized trial of the EORTC/NCIC,
which showed that radiotherapy plus concomitant and adjuvant
temozolomide significantly improved progression-free and overall
survival over radiotherapy alone. The study also provided
hypotheses about the subgroups, which are most likely to benefit
from this reasonably well tolerated regimen. In a subset of
patients, investigation of MGMT promoter methylation
in tumor tissue was performed. Survival was shorter in patients
with unmethylated promoter in both study groups. Patients
with methylated promoter treated with radiotherapy had a median
survival of 15 months, those treated with radiation plus temozolomide
of 22 months (p=0.007). In the unmethylated group, the difference
in median survival was only 1 month (p=0.06). Especially for
these patients, alternative treatments need to be developed.
The optimum schedule of temozolomide administration and the
influence of combinations with additional antineoplastic agents
remains to be studied. Early results of clinical trials addressing
these issues are presented.
[Back to top]
Topical Therapy for Actinic Keratoses: Current and Evolving
Therapies
Jeffrey M. Weinberg
[Full Text Article]
Actinic keratoses (AKs) are evolving malignant cutaneous
neoplasms. They are also known as solar keratosis, squamous
cell carcinoma in situ—solar keratotic type, or keratinocytic
intraepidermal neoplasia. Actinic keratoses can be treated
by two general methods: by physical/destructive methods and
with topical therapies. This article will review current and
evolving topical therapeutic options for AKs. Several topical
treatment options have been shown to offer some significant
benefit in the alleviation of these lesions. The therapies
include 5-fluorouracil, imiquimod, diclofenac, colchicine
and retinoids.
[Back to top]
The Development of Future Research Strategies from Reviewing
Antiemetic Trials for Chemotherapy Induced Emesis
Ian N. Olver
[Full Text Article]
In reviewing the latest trials of antiemetic usage to prevent
cytotoxic chemotherapy induced emesis, gaps in the literature
suggest directions for future research and identify methodological
approaches to be used in future investigations. The usage
of molecular techniques and the identification of new receptors
may allow new antiemetics to be developed and identification
of the genes coding for antiemetic receptors may be used to
select the appropriate antiemetics for individuals. Given
the success achieved in controlling post chemotherapy vomiting,
future studies should focus upon the control of nausea, and
measure the impact of antiemetic control on quality of life
as well as evaluating the pharmacoeconomics of these agents.
Accounting for the interaction of antiemetics with cytotoxics
becomes more important in trial design with the increasing
complexity of antiemetic regimens. More information is needed
on the emetic potential of the various combination chemotherapy
regimens, multiple day chemotherapy and chemotherapy over
multiple cycles. The emetic potential of prolonged administration
of oral chemotherapy and newer biologicals and targeted therapies
needs to be recorded. Further studies are required in specialized
areas such as with high dose chemotherapy, for radiation induced
emesis and in pediatrics.
[Back to top]
Clinical Benefit of Idiotype Vaccines: Too Many Trials
for a Clever Demonstration?
Maurizio Bendandi
[Full Text Article]
The most accepted and least biased manner to demonstrate
clinical benefit for any new treatment is to show that it
conveys a survival advantage in a well-designed phase III,
randomized clinical trial. However, in selected cases, an
exception can be made to this sound rule.
This review aims at elucidating one such example. In particular,
I intend to show that when an individualized form of immunotherapy
like idiotypic vaccination, which by definition is completely
inactive against any tumor cells, is applied to cancer patients
with indolent follicular lymphoma, a carefully crafted phase
II clinical trial may be able to demonstrate clinical benefit
better and more rapidly than a phase III alternative.
This consideration might be rather important over the next
two to three years, since the results of as many as three
ongoing phase III clinical trials on idiotype vaccines are
expected to be unveiled within this time frame, following
the release of conclusive data of our phase II clinical trial,
which is imminent.
[Back to top]
Functional Recovery After Stroke: A Review of Current Developments
in Stroke Rehabilitation Research
Boudewijn Kollen, Gert Kwakkel and Eline Lindeman
[Full Text Article]
This review article discusses current research developments
in functional recovery after stroke. With the institutionalization
of stroke services across health care facilities, a reduction
in mortality rates, length of inpatient stay and improved
independence in activities of daily living has been reported.
Several systematic reviews show that traditional treatment
approaches induce improvements that are confined to impairment
level only and do not generalize to a functional improvement
level. More recently developed treatment strategies that incorporate
compensation strategies with a strong emphasis on functional
training, may hold the key to optimal stroke rehabilitation.
Intensity and task-specific exercise therapy are important
components of such an approach. Guidelines may assist the
clinician in this responsibility. However, due to marked heterogeneity
of the stroke population and poor methodological quality of
many studies, results are uncertain. Several options are discussed
to overcome the problem of stroke heterogeneity in research
designs.
Longitudinal repeated measurements designs are required to
study the effects of non-linearity and time dependency of
functional recovery in stroke. Furthermore, prognostic research
based on sound clinimetric data generates relevant information
that may guide the clinician in clinical decision making and
in determining optimal treatment strategies.
[Back to top]
A Review of Methods for Ensuring the Comparability of Comparison
Groups in Randomized Clinical Trials
Vance W. Berger
[Full Text Article]
While different design features of medical studies ostensibly
serve different functions, many fall under the umbrella of
methods aimed at ensuring the comparability of the comparison
groups. Randomization rightly occupies the top spot in the
hierarchy of design types, as it eliminates some biases (that
is, systematic differences in comparison groups) that no other
design can claim to eliminate. It is often assumed, and sometimes
even asserted explicitly, that randomization by itself suffices
to ensure that the comparison groups are sufficiently comparable
that they would differ only randomly, but two points need
to be made in this context. First, the assertion is not true.
Second, even if it were true, it would still not be a cause
for complacency, because even random baseline imbalances can
wreak havoc on the valid interpretation of randomized clinical
trials. Additional methods, beyond randomization, are therefore
seen to be essential to the design of a good randomized clinical
trial. Such methods include masking, allocation concealment,
restrictions on the randomization, adjustment for prognostic
variables, and the intent-to-treat approach to data analysis.
Masking aims to ensure that those individuals in any one group
formed by randomization are treated as similarly as possible
subsequent to randomization as those in any other group formed
by randomization. In contrast, allocation concealment and
restricted randomization aim to create groups that start off
as comparable. Adjustment for prognostic variables aims to
change the comparison groups themselves to make them comparable.
For example, one might find gender to be both predictive of
outcome and unbalanced across treatment groups, and so one
would compare the treatment groups not overall but rather
first only among females and second only among males. The
intent-to-treat approach aims to keep similar groups similar
by not allowing for patient selection based on post-randomization
outcomes (including failure to comply with the protocol).
The key to understanding masking, allocation concealment,
and randomization is to recognize that none of them are binary
phenomena, even though they are often incorrectly understood
to be. So one must question how these methods are actually
carried out, rather than contenting oneself with the vague
statement that these methods were performed. This review will
shed light on the distinction between the process and the
outcome of each of these methods (masking, allocation concealment,
and randomization), and will also consider issues related
to adjustment for prognostic covariates.
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