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Reviews
on Recent Clinical Trials
ISSN: 1574-8871
Reviews on Recent Clinical Trials
Volume 2, Number 3, September 2007
Contents
Radiation Therapy Plus Angiogenesis Inhibition with
Bevacizumab: Rationale and Initial Experience Pp.
163-168
Carsten Nieder, Nicole Wiedenmann, Nicolaus H. Andratschke,
Sabrina T. Astner and Michael Molls
[Abstract]
Intraperitoneal Chemotherapy as Primary Treatment
of Advanced Ovarian Cancer: Efficacy, Toxicity, and Future
Directions Pp. 169-173
Maurie Markman
[Abstract]
Update on Medical and Surgical Management of Intracerebral
Hemorrhage Pp. 174-181
Raymond Tak Fai Cheung
[Abstract]
Clinical Trials of Cancer Therapies Targeting Prostate-Specific
Membrane Antigen Pp. 182-190
William C. Olson, Warren D.W. Heston and Ayyappan K. Rajasekaran
[Abstract]
Systemic Therapeutic Options in Thymic Malignancies:
A Glimmer of Hope Pp. 191-205
Lisa A. Hammond-Thelin and Charles R. Thomas, Jr.
[Abstract]
Standards and Novel Therapeutic Options in the Treatment
of Patients with Soft Tissue Sarcoma Pp. 206-211
Bernd Kasper
[Abstract]
Selective Internal Radiation Therapy with Yttrium-90
for Unresectable Liver Tumours Pp. 212-216
Malika Khodjibekova, Teresa Szyszko, Sameer Khan, Kuldip
Nijran, Paul Tait and Adil AL-Nahhas
[Abstract]
Dissection of Signal Transduction Pathways as a Tool
for the Development of Targeted Therapies of Hepatocellular
Carcinoma Pp. 217-236
Diego F. Calvisi, Rosa M. Pascale and Francesco Feo
[Abstract]
Abstracts
[Back to top]
Radiation Therapy Plus Angiogenesis Inhibition
with Bevacizumab: Rationale and Initial Experience
Carsten Nieder, Nicole Wiedenmann, Nicolaus H. Andratschke,
Sabrina T. Astner and Michael Molls
Angiogenesis inhibition by monoclonal antibodies against vascular
endothelial growth factor receptor (VEGFR) combined with cytotoxic
chemotherapy has shown encouraging potential for improvement
of cancer treatment. Several rationales exist for combining
VEGFR antibodies with ionizing radiation, a primary curative
cancer treatment, either in bimodal or trimodal fashion, i.e.
with or without additional chemotherapy. This systematic review
compares the results of preclinical and clinical studies published
before December 2006. The combination of VEGFR inhibitors
with irradiation in animal models consistently resulted in
improved tumor growth delay (at least additive effects), despite
different treatment schedules. Only one study evaluated tumor
control dose (TCD)50 as a measure of tumor cure (radiation
dose yielding permanent local control in 50% of the tumors).
Also in this setting, anti-VEGFR antibody treatment improved
the outcome. Importantly, both radiotherapy schedule and sequence
of the modalities in combined treatment may impact on the
outcome. Hence, further preclinical studies examining these
parameters need to be conducted. While preclinical research
is ongoing, phase I and II clinical trials with bevacizumab,
usually combined with radio- and chemotherapy, have been designed.
Early results suggest that acute toxicity is acceptable, planned
surgery after such treatment is feasible, and that further
evaluation of such combined modality treatment is warranted.
[Back to top]
Intraperitoneal Chemotherapy as Primary Treatment
of Advanced Ovarian Cancer: Efficacy, Toxicity, and Future
Directions
Maurie Markman
Three U.S. National Cancer Institute cooperative group randomized
phase 3 trials have demonstrated that the intraperitoneal
delivery of cisplatin-based chemotherapy as primary treatment
of small-volume residual advanced ovarian cancer improves
survival compared to the administration of all agents by the
intravenous route. As use of intraperitoneal chemotherapy
requires additional resources and expertise beyond that associated
with routine intravenous treatment, and unique side effects
may be observed (e.g., catheter malfunction, intra-abdominal
infection), some have questioned the utility of this approach,
despite the documented survival advantage. This review outlines
the data supporting intraperitoneal delivery in ovarian cancer,
discusses strategies to safely and effectively employ regional
therapy, and highlights areas where future trials are required
to optimize this novel method for treatment of this malignancy.
[Back to top]
Update on Medical and Surgical Management of Intracerebral
Hemorrhage
Raymond Tak Fai Cheung
Intracerebral hemorrhage (ICH) accounts for 15% of all strokes
in the US and Europe and 20% to 30% in Asian populations.
ICH is associated with a higher morbidity, disability and
mortality than ischemic strokes. Primary ICH originates from
spontaneous rupture of small arteries and arterioles previously
damaged by chronic hypertension or amyloid angiopathy. Secondary
ICH is associated with underlying vascular abnormalities or
other pathologies. Manifestation is acute with focal neurological
signs and features of raised intracranial pressure. Despite
our improved understanding of the pathophysiology of hematoma
expansion and edema formation, management is primarily supportive,
and outcomes remain poor. A recently published report has
confirmed that there is no overall benefit from early surgery
when compared with initial conservative treatment. In contrast,
treatment with recombinant activated factor VII within 4 hours
of onset limits hematoma growth at 24 hours, and reduces mortality
and improves functional outcomes at 90 days. Several ICH scoring
methods have recently been proposed for better prediction
of outcome. These scoring methods may be useful in selecting
suitable patients for clinical trials. Microbleeds are commonly
seen on magnetic resonance imaging. Further studies are awaited
to clarify the association between microbleeds and the future
risk of ICH.
[Back to top]
Clinical Trials of Cancer Therapies Targeting Prostate-Specific
Membrane Antigen
William C. Olson, Warren D.W. Heston and Ayyappan K. Rajasekaran
Prostate cancer is the most common non-cutaneous cancer of
men in the United States and represents their second-leading
cause of cancer-related death. Metastatic disease is largely
resistant to conventional chemotherapies, and targeted therapies
are urgently needed. Prostate-specific membrane antigen (PSMA)
is a prototypical cell-surface marker of prostate cancer.
PSMA is an integral, non-shed, type 2 membrane protein with
abundant and nearly universal expression in prostate carcinoma,
but has limited extra-prostatic expression. In addition, PSMA
is expressed in the neovasculature of other solid tumors.
These findings have spurred development of PSMA-targeted therapies
for cancer, and first-generation products have entered clinical
testing. Vaccine approaches have included recombinant protein,
nucleic acid and cell-based strategies, and anti-PSMA immune
responses have been demonstrated in the absence of significant
toxicity. Therapy with drug-conjugated and radiolabeled antibodies
has yielded objective clinical responses as measured by reductions
in serum prostate-specific antigen and/or imageable tumor
volume. However, responses were observed in a minor fraction
of patients and at doses near the maximum tolerated dose.
Overall, these initial studies have provided measured proof
of concept for PSMA-based therapies, and second-generation
antibody and vaccine products may hold the key to exploit
PSMA for molecularly targeted therapy of prostate and other
cancers.
[Back to top]
Systemic Therapeutic Options in Thymic Malignancies:
A Glimmer of Hope
Lisa A. Hammond-Thelin and Charles R. Thomas, Jr.
Progress in the systemic therapy of thymic malignancies has
been hampered in the past by the rarity of this disease entity
and the lack of a global collaborative effort in conducting
phase II studies. Cisplatin-based therapy has been considered
the standard of care, though data typically has been derived
from a retrospective case-series approach. However, the arrival
of novel cytotoxic agents and molecularly targeted agents
into the clinic has helped provide the impetus for improved
methodology in thymic malignancy research with an emphasis
on more prospective phase II studies. This review discusses
the results of traditional cytotoxic agents, novel cytotoxic
agents, biologic therapy and the initial evaluation of molecularly
targeted therapeutics, such as epidermal growth factor receptor
inhibitors, for the treatment of thymic malignancies. In addition,
potential novel targets such as VEGF, Bcl-2 and c-KIT are
assessed.
[Back to top]
Standards and Novel Therapeutic Options in the Treatment
of Patients with Soft Tissue Sarcoma
Bernd Kasper
Soft tissue sarcomas are a heterogeneous group of tumours
arising predominantly from the embryonic mesoderm. They account
for less than 1 % of all adult malignancies. The prognosis
of patients with advanced metastatic soft tissue sarcoma remains
poor with a disease-free survival at 5 years less than 10
%. Despite improvements in local tumour control due to surgery
and radiotherapy, distant metastasis and death remain a significant
problem in 50 % of patients. Complete resection remains the
major factor in providing cure with limited benefits in local
tumour control by radiotherapy and only minimal benefit of
systemic therapy for metastatic disease. Only few chemotherapeutic
agents have been identified to be active with reported response
rates for doxorubicin and ifosfamide around 20 %. New strategies
are urgently needed to improve patients’ outcome. Progress
in the molecular characteristics, the understanding of biology
and pathogenesis of these tumours has been made and should
in the near future translate into molecularly based therapies.
We describe current treatment strategies and existing standards.
Moreover, we give an overview on the emerging compounds for
patients with soft tissue sarcoma including recent developments
of targeted therapy focusing on antiangiogenic and immunomodulatory
drugs, Bcl-2 antisense therapy, raf kinase and mTOR inhibition,
minor groove binders, and other agents being developed.
[Back to top]
Selective Internal Radiation Therapy with Yttrium-90
for Unresectable Liver Tumours
Malika Khodjibekova, Teresa Szyszko, Sameer Khan, Kuldip
Nijran, Paul Tait and Adil AL-Nahhas
Primary and secondary liver tumours are common malignancies
that are being treated more aggressively now-adays than decades
ago. Surgery is the most effective method of treatment but
is only suitable for a minority of patients with well-defined
and easily accessible tumours. Surgical resection is contraindicated
in patients with massive involve-ment of the liver or in cases
where the disease involves the confluence of vessels at the
porta hepatis. These patients may benefit from a variety of
ablative and embolic therapies including selective internal
radiation therapy (SIRT) with Yttrium-90 microspheres. SIRT
has been introduced in the 1980’s but the technology
has been refined and made more available only recently. The
microspheres are injected directly into the hepatic arteries,
through a trans-femoral angiographic approach, and are delivered
selectively to tumours due to their preferential blood supply
by hepatic arteries. SIRT can therefore target small volumes
disease with a higher dose of radiation compared with external-beam
radiation and is associated the relatively low toxicity and
a good response irrespective of tumor origin. Assessment of
response to therapy is best performed with metabolic imaging
using 18F-FDG
PET scanning.
Although it is not considered as a cure, it has been shown
to improve quality of life and prolong survival, with the
main cause of death being extra-hepatic spread. The technical
and clinical demands of patient selection, treatment planning,
administration, and clinical follow-up require an interdisciplinary
team willing to work cooperatively to achieve the best result
for the patient.
[Back to top]
Dissection of Signal Transduction Pathways as a Tool
for the Development of Targeted Therapies of Hepatocellular
Carcinoma
Diego F. Calvisi, Rosa M. Pascale and Francesco Feo
Genomic instability during hepatocarcinogenesis causes changes
in signal transduction network. Strategies for identification
of new markers/therapeutic targets include discovery of early
molecular changes during hepatocarcinogenesis, relevant to
preneoplastic lesions progression to full malignancy in rodent
models, and evaluation of these changes in human hepatocellular
carcinomas (HCCs). Activation of ERB receptor family,
MAPK, JAK-STAT, β-Catenin
cascades, c-Myc targets, iNOS-IKK/MAT1A-NF-kB axis, Ornithine
decarboxylase, Cyclins and CDKs occurs in human and rodent
hepatocarcinogenesis. This is associated with downregulation
of the cell cycle inhibitors p16INK4A
and p53 and TGF-β/SMAD
signaling. Oncosuppressor genes, including p16INK4A,
E-CAD, and DLC-1 are often hypermethylated in humans and rodents.
Moreover, protection of cell cycle from p16INK4A
inhibition by upregulation of CDC37, HSP90, and CRM1 correlates
to HCC progression. A body of evidence indicates that inhibition
of key genes of aforementioned signaling path-ways by antisense
or siRNA approaches or specific inhibitors restraints growth
of in vitro cultured or in vivo xenografted
HCCs. Efforts are currently dedicated to improve transduction
efficiency. HCC cells may escape gene therapy by various mechanisms.
Attempts to overcome this difficulty include discovery of
new therapeutic targets, gene therapy directed to different
molecular targets essential for tumor cell survival and specifically
directed to HCC subtypes.
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