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Reviews
on Recent Clinical Trials
ISSN: 1574-8871
Reviews on Recent Clinical Trials
Volume 3, Number 3, September 2008
Contents
Targeted Therapies in Head and Neck Cancer: Past,
Present and Future Pp. 156-166
Alexander D. Rapidis, Jan B.Vermorken and Jean Bourhis
[Abstract]
Manipulation of Intestinal Microbial Flora for
Therapeutic Benefit in Inflammatory Bowel Diseases: Review
of Clinical Trials of Probiotics, Prebiotics and Synbiotics
Pp. 167-184
Debra Heilpern and Andrew Szilagyi
[Abstract]
Clinical Trials of Targeted Alpha Therapy for
Cancer Pp. 185-191
Barry J. Allen
[Abstract]
Chromatin Remodeling Agents for Cancer Therapy
Pp. 192-203
La Sala Dario, Magnano Anna Rosa, Estenoz Mariela, Giordano
Roberto and Cinti Caterina
[Abstract]
Chemotherapy in Addition to Preoperative Radiotherapy
in Locally Advanced Rectal Cancer – A Systematic Overview
Pp. 204-211
Bengt Glimelius, Torbjörn Holm and Lennart Blomqvist
[Abstract]
Novel Therapeutic Options in Metastatic Renal Cancer
– Review and Post ASCO 2007 Update Pp. 212-216
Stephan Kruck, Markus A. Kuczyk, Georgios Gakis, Mario
W. Kramer, Arnulf Stenzl and Axel S. Merseburger
[Abstract]
The Role of Cetuximab and Other Epidermal Growth Factor
Receptor Monoclonal Antibodies in the Treatment of Advanced
Non-Small Cell Lung Cancer Pp. 217-227
Antonio Rossi, Emilio Bria, Paolo Maione, Giovanni Palazzolo,
Marzia Falanga and Cesare Gridelli
[Abstract]
Current Status and Perspectives Regarding the
Treatment of Osteosarcoma: Chemotherapy Pp. 228-231
Akio Sakamoto and Yukihide Iwamoto
[Abstract]
Abstracts
[Back to top]
Targeted Therapies in Head and Neck Cancer: Past, Present
and Future
Alexander D. Rapidis, Jan B.Vermorken and Jean Bourhis
Head and neck cancers remain a significant health
problem globally. The addition of chemotherapy to radiotherapy
for locoregionally advanced squamous cell carcinoma of the
head and neck (SCCHN) has led to improvements in locoregional
disease control and in survival, but is associated with substantial
acute and late toxicities. In recurrent and/or metastatic
SCCHN, there have been no improvements in survival, despite
the manipulation of standard therapeutic regimens and the
introduction of newer cytotoxic agents. Over the last decade,
targeted therapies have been increasingly used in a range
of solid tumor types. This article discusses the clinical
evidence for the use of a number of targeted agents in the
treatment of locoregionally advanced and recurrent and/or
metastatic SCCHN. The article focuses on the epidermal growth
factor receptor (EGFR) inhibitors, for which the majority
of clinical information is available. These include the monoclonal
antibody (MAb) cetuximab and the tyrosine kinase inhibitors,
erlotinib and gefitinib. Clinical data for the vascular endothelial
growth factor (VEGF) inhibitor, bevacizumab, are also presented.
[Back to top]
Manipulation of Intestinal Microbial Flora for Therapeutic
Benefit in Inflammatory Bowel Diseases: Review of Clinical
Trials of Probiotics, Prebiotics and Synbiotics
Debra Heilpern and Andrew Szilagyi
Pathogenesis of Inflammatory Bowel Diseases(Ulcerative
Colitis, Crohn’s disease and Pouchitis) includes an
abnormal immunological response to disturbed intestinal microflora.
Therapeutic strategies are designed to intervene in these
abnormal host microbial communications. A novel approach in
the last decade has been to use other bacteria or selective
foods to induce beneficial bacteria to normalize inflammation.
In this review we discuss rationale for such use and describe
46 clinical trials gleaned from the literature. Reports are
divided into type, indications, and agents used. The search
revealed 15 nonrandomized and 31 randomized trials. Of the
latter 23 were double-blind and 8 were open-label randomized
controlled. In 32 of the total, different probiotics were
used, while 10 and 4 used different prebiotics or synbiotics
respectively. In 14 nonrandomized trials, outcome was successful.
In the randomized controlled trials 12 of 16 ulcerative colitis
but only 2 of Crohn’s disease trials of biotic therapy
were successful. No superiority of any probiotic was clearly
evident, but a multi-agent mixture, VSL3# may be better suited
in ulcerative colitis and pouchitis while the probiotic Lactobacillus
rhamnosus GG appears less useful in inflammatory bowel disease,
especially Crohn’s disease. Further studies with uniform
stringent criteria are needed to provide proof of this therapy
in inflammatory bowel disease.
[Back to top]
Clinical Trials of Targeted Alpha Therapy for Cancer
Barry J. Allen
Targeted alpha therapy is an advancing experimental therapy
that holds promise to deliver high cytotoxicity to targeted
cancer cells. Initially thought to be indicated for leukaemia
and micrometastases, there is now evidence that solid tumours
can also be regressed.
Alpha therapy may be molecular or physiological in its targeting.
Alpha emitting radioisotopes such as Bi-212, Bi-213, At-211
and Ac-225 are used to label monoclonal antibodies or proteins
that target specific cancer cells. Alternatively, radium-233
is used for palliative therapy of breast and prostate cancers
as it is a bone seeking element.
Progress in the development of clinical trials of alpha therapy
is examined for leukaemia, lymphoma, melanoma, glioblastoma
multiforme, bone metastases, ovarian cancer, pancreatic cancer
and other cancers. Results of past and current trials are
reviewed, and the bases of some proposed trials are presented.
[Back to top]
Chromatin Remodeling Agents for Cancer Therapy
La Sala Dario, Magnano Anna Rosa, Estenoz Mariela, Giordano
Roberto and Cinti Caterina
Alterations in chromatin structure profoundly influence
gene expression during normal cellular homeostasis and malignant
transformation. Methylation of cytosines within CpG islands
located in promoter and proximal coding regions facilitates
recruitment of chromatin-remodeling proteins, which inhibits
gene expression. Posttranslational modifications, such as
acetylation, methylation, and phosphorylation, of core histone
proteins ‘‘mark’’ regions of chromatin
for recognition by multiprotein complexes, which promote either
chromatin relaxation and gene expression or chromatin compaction
and repression of gene expression. Many genes become transcriptionally
silenced during the development of cancer. Covalent epigenetic
modifications such as DNA hypermethylation and histone post-translational
modifications are an important early event during carcinogenesis
and tumor development. Genes involved in key DNA damage responses
pathways, apoptosis signaling and DNA repair, can frequently
become methylated and epigenetically silenced in tumors. This
may lead to differences in intrinsic sensitivity of tumors
to chemotherapy, depending on the specific function of the
gene inactivated. The fact that cancer can have an epigenetic
etiology has encouraged the development of a new therapeutic
option that might be termed “epigenetic therapy”.
The DNA methylation paradox, manifested as derepression of
cancertestis antigens and silencing of tumor suppressors during
malignant transformation, provides rationale for the utilization
of chromatin remodeling agents for cancer therapy. In this
review, the recent advances in the understanding and clinical
development of DNA methyltransferase and Histone deacetylase
inhibitors, as well as their current role in cancer therapy,
will be discussed.
[Back to top]
Chemotherapy in Addition to Preoperative Radiotherapy in Locally
Advanced Rectal Cancer – A Systematic Overview
Bengt Glimelius, Torbjörn Holm and Lennart Blomqvist
The value of chemotherapy with radiotherapy has been
explored in recent randomised clinical trials in locally advanced
rectal cancer (LARC). An overview of these trials was made
together with a discussion of what constitutes LARC. Although
imaging is required for adequate staging of primary rectal
cancer, the term ´locally advanced´ has no consistent
definition and has been used differently in the trials. Three
large randomised trials, however, in different subsets, show
that radiochemotherapy (RTCT) with 5-FU-based treatment compared
to the same radiotherapy (RT) improves local control and has
some influence on systemic relapses and possibly overall survival,
without being too toxic. Whether the chemotherapy acts as
a radiosensitizer is not known. Preoperative short-course
RT alone (5 x 5 Gy) had in one trial similar activity as preoperative
RTCT and less toxicity and was, in another trial, superior
to selectively given postoperative RTCT. In conclusion, preoperative
RTCT, using 5-FU is a new evidence-based treatment in the
most locally advanced rectal cancers (T4 tumours growing into
neighbouring organs), whereas its use in the slightly less
advanced cancers could be discussed. Several phase I –
II trials have indicated that combinations of drugs with RT
can be even more efficient, but this must be proven in randomised
trials since patient selection is of great importance.
[Back to top]
Novel Therapeutic Options in Metastatic Renal Cancer –
Review and Post ASCO 2007 Update
Stephan Kruck, Markus A. Kuczyk, Georgios Gakis, Mario
W. Kramer, Arnulf Stenzl and Axel S. Merseburger
Cytokine-based therapeutic approaches using interferon
(IFN) and interleukin 2 (IL-2) were conventionally applied
for the treatment of progressive RCC. Caused by the limited
effectiveness of cytokine-based approaches in advanced renal
cell carcinoma, new substances were needed. Among these, the
"targeted therapies", particularly the group of
the tyrosine kinase inhibitors, are of main interest. At present,
multikinase inhibitors and antiangiogenic agents (VEGFR, PDGFR-beta,
and mTOR) are used in first- and secondline therapies of metastatic
RCC in various clinical studies. This review presents and
discusses the effectiveness of the most frequently used substances
in mono- or combination regimes based on current data of the
ASCO 2007.
[Back to top]
The Role of Cetuximab and Other Epidermal Growth Factor Receptor
Monoclonal Antibodies in the Treatment of Advanced Non-Small
Cell Lung Cancer
Antonio Rossi, Emilio Bria, Paolo Maione, Giovanni Palazzolo,
Marzia Falanga and Cesare Gridelli
Lung cancer continues to be the leading cause of
cancer-related deaths in the western civilization and developing
countries. Non-small cell lung cancer (NSCLC) accounts for
> 85% of all cases of lung cancer. Since most patients
with NSCLC have advanced disease at diagnosis, to date chemotherapy
with third-generation platinum-based doublets represents the
standard of care. However, a plateau has been reached with
the use of cytotoxic chemotherapy in advanced NSCLC. Advances
in the knowledge of tumour biology and mechanisms of oncogenesis
have granted the singling out of several molecular targets
for NSCLC treatment. In particular, the epidermal growth factor
receptor (EGFR), a member of the ErbB family and commonly
overexpressed in NSCLC, is one of the most studied targets.
Overexpression of EGFR has been associated with a poorer prognosis
in patients with cancer, therefore its inhibition may lead
to the suppression of tumor proliferation improving clinical
outcome. Strategies to block EGFR include development of monoclonal
antibodies to EGFR, tyrosine kinase inhibitors, ligand-linked
toxins, and antisense approaches. This article will focus
on cetuximab and other monoclonal antibodies and their applications
in the treatment of advanced NSCLC.
[Back to top]
Current Status and Perspectives Regarding the Treatment of
Osteosarcoma: Chemotherapy
Akio Sakamoto and Yukihide Iwamoto
Osteosarcoma is the most common primary bone tumor
in childhood and adolescence. The use of combination chemotherapy
and surgery enables long-term survival in approximately 60-70%
of cases. However, the necessity for surgery, the poor prognosis
of patients with metastatic or recurrent disease (long-term
survival in only about 20% of cases), and the lack of establishment
of second-line chemotherapy suggest that improvements in chemotherapy
are desperately needed. Currently, in an effort to extend
the protocol with the chemotherapy drugs that already exist,
high-dose chemo-therapy with/without autologous peripheral
blood stem cell transplantation, and tumor-targeted drug delivery
systems are under investigation. Future drug developments
will no doubt lie in the direction of immunotherapy and anti-angiogenic
therapy, as well as the use of cytotoxic drugs. Identifying
the genes and signal transduction pathways responsible for
the development of osteosarcoma or for the occurrence of malignancy
in cases of osteosarcoma will undoubtedly lead to the identification
of pathway-specific agents, or possible gene therapy. Furthermore,
as increased light is shed on the character of osetoblastic
differentiation in osteosarcoma, this will certainly give
rise to new treatments utilizing differentiation therapy.
This article reviews the current status and perspectives regarding
the treatment of osteosarcoma in terms of chemotherapy.
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