Innovations in chemotherapy and radiation therapy: Implications and opportunities for the Asia-Pacific Rim
1 Department of Radiation Oncology, University of
Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, United States
2 Department of Medical Oncology, UPMC Cancer Centers, Pittsburgh, Pennsylvania, United States
New cases of invasive cancer in the United States occur among nearly 1.5 million people annually. In 2007, more than 1,500
people died per day with this diagnosis. Cancer is responsible for nearly one
in every four deaths reported in the country. Enormous amounts of money and
research have been, and are being spent, in an attempt to improve these
numbers. While prevention and early detection remain the key to long-term
success, treatment in the neo-adjuvant, adjuvant and metastatic settings still
centre around two main treatment modalities � radiation therapy and
chemotherapy. This article will review the advances that have been made in both
areas that are making these treatments more precise and convenient, as well as
less toxic, for the patient. In the field of radiation therapy this involves
the development of new therapy planning and delivery systems, such as
intensity-modulated radiation therapy (IMRT), and positron emission and
computed tomography, PET-CT. Chemotherapy has also evolved with the development
of targeted chemotherapy for the treatment of specific malignancies as well as
improved supportive care agents which allow for the administration of
dose-dense chemotherapy when appropriate. � 2008 Biomedical Imaging and
Intervention Journal. All rights reserved.
Keywords: Cancer, radiation therapy, chemotherapy, supportive
The number of new cancer patients diagnosed in the United States in 2007 was 1,444,920, excluding patients with carcinoma in situ (except of
the bladder) and either squamous or basal cell carcinoma of the skin. The
number of deaths attributed to a cancer diagnosis in 2007 was 559,650, or more
than 1,500 people per day. Cancer is second only to heart disease as the
leading cause of death in the country and is responsible for 1 in every 4
While those statistics are quite grim, the 5-year survival
rate for all cancers diagnosed was reported to be 66% in the last years of
reporting � 1996 through 2002 � which is up substantially from the mid-1970�s
when the number hovered around 50% . Unfortunately, these improvements are
not noted in every cancer, nor in every patient based upon age, race or sex.
There are a number of reasons for this dramatic improvement including, but not
limited to, the advances in detection and treatment of the disease as well as
improved supportive care drugs and an improved understanding of the molecular
changes which may contribute to the development of a malignancy. These numbers
will only improve when the data since 2002 becomes available.
The most common malignancies for women in the U.S. as of 2007 are breast cancer (178,480), lung cancer (98,620) and colorectal cancer
(74,630). The death rates associated with these malignancies are 70,880
patients with lung cancer, 40,460 patients with breast cancer, and 26,180 with
colorectal cancer. The most common malignancies for U.S. males during the same
time period were prostate cancer (218,890), lung cancer (114,760) and
colorectal cancer (79,130). Lung cancer was responsible for the highest number
of deaths at 89,510, followed by prostate cancer at 27,050 and colorectal
cancer at 26,000. .
The cost of cancer in the U.S. is staggering. For 2006,
the National Institutes of Health estimated the overall cost of cancer at
USD$206.3 billion. Direct medical costs accounted for USD$78.2 billion,
indirect mortality costs (cost of loss productivity due to illness) USD$17.9
billion, and indirect mortality costs (cost of lost productivity due to
premature death) USD$110.2 billion .
The treatment of cancer has revolved around three specific
treatment modalities � surgery , radiation [3,4] and chemotherapy .
Depending upon the malignancy, stage at diagnosis and ultimate treatment goal
(cure versus palliation) one, two or all three of these treatment modalities
may be utilised.
This paper will review the innovations in radiation
therapy and chemotherapy.
Radiation Therapy Background
Radiation therapy remains one of the most potent therapies
in the fight against a variety of cancers. In the last decade, tremendous
advances have heralded technological innovations that make treatments more
precise, convenient and with less toxicity. The integration of advanced imaging
such as magnetic resonance (MRI), positron emission and computed tomography (PET-CT)
along with other functional imaging modalities has augmented the
individualisation of each patient�s radiation therapy plan. In doing so, each
patient�s unique plan can be optimised to meet the individual goals of
In previous decades, radiation teletherapy was delivered
via rudimentary techniques using radioactive sources (e.g. Cobalt-60) mounted
in a gantry head. This form of radiation therapy is still widely used in many
parts of the developing world today where access to reliable electricity is
problematic. The rapid pace of development in Asia presents the opportunity for
the implementation of advanced radiotherapeutic techniques. A multidisciplinary
approach to cancer care will require education, effective screening and
prevention, as well as monetary and staff investment .
Radiation Therapy Delivery & Planning Systems
The development of the linear accelerator at Stanford University in the early 1970�s ushered in an era of highly complex plans aided by
highly sophisticated computer controls [7-9]. These complex controls have
facilitated the implementation of three-dimensional conformal radiation therapy
(3D-CRT). The goal of 3D-CRT is to deliver a highly complex combination of
radiation beam angles and field shapes using CT-based dataset to define the
target volumes for treatment and avoidance of nearby critical structures.
Although not formally and rigorously tested in any randomised trials (versus
2-dimensional radiation therapy), this technique has resulted in a
significantly improved target definition [10,11] and reduction in
treatment-related complications [12-16]. The introduction of the multi-leaf
collimator (MLC), a computer-controlled beam shaping device, has increased the
efficiency of conformal therapy and offered several advantages over cerrobend
block designs. Dynamic shaping of the radiation beam using small, mobile
tungsten leaves has enabled modulation of the radiation beam. Beam modulation
can be achieved by slowing the movement of the MLC in areas where larger doses
are to be delivered compared to those areas that require protection (e.g.
spinal cord). The result of these dose distributions in serial adjacent axial
slices is the desired conformal radiation plan. The composite result of this
technique is the hallmark of intensity-modulated radiation therapy (IMRT). An
example of IMRT used to treat a cervical cancer with para-aortic disease is
depicted in Figure 1.
Clinical outcomes of IMRT have consistently demonstrated
improvement in clinical endpoints in patients with lung cancer, intracranial
tumours, prostate, gynaecologic and head and neck cancers [17-31]. Although the
outcomes are quite compelling, clinical implementation of IMRT remains a major
rate limiting step in a variety of practice settings. Although most modern
linear accelerators are equipped to deliver IMRT, very few have delivered these
treatments. The main barrier to the implementation of these advanced programmes
is still the lack of clinical training and professional development of the
clinical staff, i.e. radiation oncologist, physicist and/or dosimetrist. The
labour intensive nature of IMRT planning further compounds the implementation
of these programmes in many small, medium and large centres. Furthermore,
careful training and implementation of quality assurance processes are critical
and should be reassessed on a routine basis.
Imaging and Image-guided Radiation Therapy
The introduction of computed tomography in radiation
therapy in the early 1980�s was used in the era of 3D image-guided radiation
therapy. With advances in computing power, complex algorithms that better model
the radiation beam�s interaction with tissues have further refined our ability
to predict the radiation distribution and predict the likely toxicities of
treatment. Accurate definition of the target volume has become increasingly
important as we seek to improve locoregional control rates while reducing the
toxicities typically seen with modern cancer treatments. Multi-modality fusion
of various imaging modalities such as computed tomography (CT), magnetic
resonance imaging (MRI), positron emission tomography (PET), single-positron
emission computed tomography (SPECT), amongst others, now provides a wealth of
functional, biological and physiological data. For example, this information can
now be exploited to target metabolic active or hypoxic areas of tumours. The
clinical impact of these systems has been reported [25, 32, 33] and can be used
to design complex individualised treatment plans.
A special application of CT involves time-resolution of a
moving target such as lung cancer. Compensation of physiologic organ motion is
critical in highly-conformal radiation therapy. Failure to account for target
or organ motion may result in unacceptable under-dosing of the cancer or fatal
irradiation of an organ or critical structure. However, after accounting for
these physiological motions, individualised margins can be used to
significantly reduce complications of treatment by reducing the dose delivered
to uninvolved tissues while offering the opportunity to improve local control
rates [13-36]. Four-dimensional computed tomography (4D-CT) now allows
clinicians to better assess the tumour or organ�s trajectory in near
�real-time� so that each patient�s radiation plan can be individualised to the
characteristics of each situation.
Functional imaging such as magnetic resonance spectroscopy
(MRS) and positron emission tomography-computed tomography (PET-CT) has opened
new frontiers in the characterisation of tumours and their unique features. For
example, in PET-CT imaging, the metabolic function using fluorodeoxyglucose
(FDG), hypoxia using F-Misonidazole (F-Miso) or proliferation using
fluoro-thymidine (FLT) can provide valuable targets for which targeted systemic
agents or radiotherapeutic techniques. A summary of PET-CT tracers can be found
in Table 1.
Additionally, current linear accelerator technology has
rapidly evolved to incorporate on-board imaging (OBI) which allows for the
daily localisation of the radiation target volume. These systems in their
current iterations use either the linear accelerator�s megavoltage beam or a
separate kilovoltage (kV) source add-on the gantry of the linac. This
technology generates near diagnostic quality images to improve the precision
and accuracy of patient positioning and treatment verification [37-39]. The
most significant feature of OBI system is its ability to use the kV source to
produce volumetric CT images immediately prior to each dose of radiation
treatment. These acquired images can be compared to the patient�s initial CT
dataset upon which their treatment plan was created and adjustments made to the
patient�s position to ensure the accurate targeting of the radiation beam. Only
now, with the development of these new technologies, has the door been open to
near real-time adaptive radiation therapy based on target location and shape
over time. There remains significant work to be done to develop guidelines on
the specific timing, frequency and the degree of adjustment that should be made
based on the dynamic changes that will undoubtedly be seen when image-guided
radiation therapy is more broadly adopted. Additionally, despite these new
tools that may allow for more precise targeting of disease, operator
limitations and multi-modality image fusion registration uncertainties are
clear limitations and pose challenges to the implementation of these advanced
Implications for Modern Therapy in Asia
The World Cancer Report, the most comprehensive global
examination of the disease to date, was compiled in 2003 by the World Health
Organization (WHO) IARC . In that report, cancer rates are projected to
increase by approximately 50% by the year 2020. In Asia, the increase is
expected to outpace the worldwide average at 60% to 7.1 million cases per year.
The annual incidence will climb by 45% to 163 cases per 100,000 people by 2030,
from 112 cases per 100,000 population in 2005. Tobacco use, alcohol abuse and
the global rise in obesity have been identified as the leading cause of the
expected rise in these rates. This is further complicated by a rising life
expectancy and an aging population in Asia. Previously, the cancer-specific
death rate was lower in developing countries such as those in Asia,
predominantly due to infectious diseases. Furthermore, the mix of cancer cases
appears to be different in Asia compared to the Western world.
Lung cancer, which accounts for the largest number of
cancer-related deaths, is expected to increase in incidence, further outpacing
gastric cancer as the second most-common cancer with 1.2 million deaths over a
10-year period from 2005-2015 [WHO IARC report] . The increasing
Westernisation of the Asian diet is expected to drive a similar increase in
breast, rectal and colon cancer.
To treat the expected rise in incidence of cancer, more
sophisticated technologies will need to be brought to bear in the fight against
the cancer. The vast majority of external beam systems in the developing world,
including most of Asia, use ionising radiation from a Cobalt-60 source.
Although these systems are quite reliable, especially in areas lacking reliable
electrical power grid, they are unable to deliver the sophisticated radiation
therapy described above. As the rapid pace of development of these countries
unfolds and the growth rate of cancer incidence is realised, there will be a
great need to deploy these new methods into clinical practice.
Challenges for Implementation of Advanced Cancer Care in Asia
Tatsuzki and Levin in 2001 clearly document a number of
the challenges facing countries in the Far East in caring for cancer patients
. This survey-based report of 17 countries in South Asia, Southeast Asia,
East Asia and Australia revealed large differences in equipment and personnel.
For effective use of radiotherapy, there must be a planned education programme
for the general public and for referring doctors. Radiotherapy must be a part
of a multidisciplinary cancer care programme. The availability of teletherapy
and brachytherapy services were clearly based on the economic status of the
countries examined. In many countries, patients were treated with CT or
fluoroscopy-based systems. Treatment planning is also quite basic and often was
performed without computers. The availability of radiation oncologists or
cancer specialists further complicates the disparity of cancer care often
encountered in these countries .
The field of radiation oncology has undergone a remarkable
transformation in technology and processes that have enhanced the therapeutic
ratio since the discovery of x-rays nearly 100 years ago. As an increasing
number of countries in the Far East encounter the increasing incidence of a
variety of cancers, the implementation of advanced radiotherapeutic techniques
will be critical in reducing treatment-related toxicities. There is a great
need for professional staff training if the potential of these advances are to
be fully realised.
Chemotherapy has changed a great deal over the past
several years due to an improved understanding of the human genome as well as
the molecular nature of cancer.
Treatment even in the early twenty-first century centered
around the administration of large doses of cytotoxic chemotherapy agent(s)
that affected any actively dividing cell within the body whether it be
malignant or normal . In some cases, this led to the eradication of the
cancer but not without significant toxicity including life-threatening
neutropenia and thrombocytopenia, mucositis, alopecia and neuropathy .
Targeted chemotherapy for the treatment of a malignancy
was initiated with the US Food and Drug Administration (FDA) approval of
trastuzumab (Herceptin�) in September of 1998. Targeted chemotherapy drugs
specifically attack the malignant cell line, leaving most normal cells
unharmed. These therapies can be more effective and cause fewer side effects
than standard cytotoxic chemotherapeutic agents. Trastuzumab is a humanised
IgG1-kappa monoclonal antibody that selectively binds with high affinity to the
extracellular domain of the human epidermal growth factor receptor 2 protein or
HER-2 . HER-2 has been found to be over-expressed in 20-25% of all women
with breast cancer. Trastuzumab is a mediator of anti-body-dependent cellular cytotoxicity
(ADCC). This trastuzumab-mediated ADCC has been shown to be preferentially
exerted on HER-2 over-expressing cancer cells compared to other cells,
including cancer cells that do not over-express HER2. The specificity of
trastuzumab for cells which over-express HER-2 dramatically decreases the
toxicity of the drug to normal cells. The common side effects associated with
the administration of non-specific chemotherapeutic agents such as
myelosuppression, mucositis and alopecia are not associated with the
administration of trastuzumab. That is not to say that the drug is devoid of
all toxicity, however. Infusion reactions, including dyspnea, hypotension and
anaphylaxis have been reported with the use of the drug and all monoclonal
antibodies, but are rare and manageable. Cardiomyopathy as evidenced by
sub-clinical and clinical congestive heart failure and a decrease in left
ventricular ejection fraction (LVEF) has been noted particularly in patients
who receive trastuzumab with a concurrently administered anthracycline such as
doxorubicin, an agent with recognised cardiac toxicity . The cardiomyopathy
associated with patients receiving an anthracycline in combination with
trastuzumab is a late complication of therapy. While the dose-dependent cardiac
toxicity of anthracyclines is well established , it is unclear at this
point in time whether the same can be said for the continued use of single
agent trastuzumab. A review of the spectrum and reversibility of the
cardiotoxicity observed in the adjuvant trastuzumab trials was recently
reported . Up to 4% of patients enrolled onto adjuvant trastuzumab trials
experienced severe congestive heart failure during treatment with a larger
proportion of patients experiencing a sustained decrease in their left
ventricular ejection fraction to less than 50%. Studies are ongoing to better
characterise whether or not this is a dose-dependent event.
Lapatinib  is an oral tyrosine kinase inhibitor (TKI)
which acts at both the epidermal growth factor (ErbB1) and the HER2 (ErbB2)
receptor sites. It binds reversibly to tyrosine kinase blocking phosphorylation
and activation of downstream secondary messengers thereby regulating the
proliferation and survival in ErbB1 and HER2 expressing tumours. It is
currently FDA-approved in combination with the oral pyrimidine analogue
capecitabine for the treatment of patients with HER2 over-expressing advanced
or metastatic breast cancer who have received previous therapy with an
anthracycline, a taxane and trastuzumab .
Lapatinib, being a small molecule, has been shown to
penetrate the blood brain barrier and is now being evaluated as a potential
treatment in patients with metastatic breast cancer with brain involvement
Phase I data on the combination of trastuzumab and
lapatinib has recently been published . Since trastuzumab targets the
extracellular domain of HER2 (ErbB2) and lapatinib acts intracellularly with
specificity for both the ErbB1 and ErbB2 receptors, this combination may prove
to be of value in patients with HER2 (+) breast cancer. Patients were treated
with escalating doses of lapatinib, 750 to 1500 mg administered orally once
daily, in combination with trastuzumab at the standard dose of a 4 mg/kg IV
loading dose followed by a 2 mg/kg weekly maintenance dose. The primary
endpoint of the study was to assess the safety, clinical feasibility, optimally
tolerated regimen (OTR), pharmacokinetics and preliminary activity. The OTR of
the combination was lapatinib 1000 mg per day with standard weekly trastuzumab.
The most frequent grade 3 drug related toxicities were diarrhoea, fatigue and
rash. Of the 54 patients treated, all of whom were heavily pretreated, one
patient achieved a complete response and an additional seven patients had a
partial response. The authors concluded that the combination of trastuzumab and
lapatinib at the doses listed above was well tolerated and clinically active in
this patient population.
O�Shaughnessy et al. conducted the first Phase III
randomised open-labeled, multi-centered study evaluating lapatinib versus
lapatinib + trastuzumab in heavily pre-treated women with HER2+ metastatic
breast cancer. Preliminary results were reported at the 2008 American Society
of Clinical Oncology (ASCO) meeting in Chicago . Two hundred and ninety six
women were randomised and the average prior number of chemotherapy regimens was
6. Progression-free survival (12.0 weeks vs. 8.4 weeks; p=0.029) and clinical
benefit at 24 weeks (25.2% vs. 13.2%; p=0.020) both favoured the combination
therapy. There was also a trend towards a higher response rate (10.3% vs. 6.9%)
and overall survival (51.6 weeks vs. 39 weeks) in those patients treated with
the combination of lapatinib and trastuzumab. The full manuscript of this
important study will be published in the near future.
An investigational agent that shows great promise in the
treatment of a number of malignancies is pertuzumab . It is a recombinant
humanised monoclonal antibody which binds to the extracellular domain II of the
HER2 receptor and blocks its ability to dimerise with other HER receptors.
Dimerisation, or the pairing with other receptor proteins, is essential for HER
receptor activity and may well play a role in the growth and survival of cancer
cells. This activity is distinctly different from other monoclonal antibodies
such as trastuzumab or the tyrosine kinase inhibitors such as erlotinib. The
Phase I study of the drug in patients with advanced cancer has shown the drug
to be well tolerated, have clinical activity in a variety of tumour types and a
pharmacokinetic profile which allows for a 3-week dosing interval. Additional
studies are ongoing particularly in patients with metastatic breast cancer.
Other malignancies which have been treated very
effectively with targeted chemotherapy include chronic myelogenous leukaemia
(CML) and gastrointestinal stromal tumours (GIST), both with the oral agent
A list of other FDA approved targeted therapy for the
treatment of cancer in the US is shown in Table 2.
Improvements in Supportive Care
Besides the dramatic increase in the number of new,
targeted therapies, the majority of which have less toxicity than the older
cytotoxic agents, supportive care has also improved the tolerability of
chemotherapy administration. The major advances have come in the areas of
anti-emetics, growth factor support and bone health.
New classes of anti-emetics, such as the serotonin (5-HT3)
receptor antagonists and neuro-kinin 1 (NK-1) antagonists, have played a major
role in decreasing the incidence and severity of chemotherapy-induced nausea
and vomiting (CINV). See Table 3.
Combination therapy with members from each of these
classes along with a steroid, usually dexamethasone, have become the standard
of care for patients receiving moderately or highly emetogenic chemotherapy.
Growth factor support (see Table 4), particularly white
cell factors, has allowed for an increase in dose intensity which is a primary
treatment end point for patients with early stage breast cancer and lymphomas
and may also play a role in other malignancies. The advent of long acting
factors such as pegfilgrastim have allowed for a single dose of the growth
factor per cycle versus daily subcutaneous administration for 7-10 days as was
usually seen with filgrastim or sargramostim. The red cell growth factors have
allowed for a decrease in the need for red blood cell transfusions in patients
actively being treated for their malignancies. Recent studies have shown an
increase in risk of thrombosis and death if these agents are used to increase
haemoglobin levels to greater than 12 gm/dl in some groups of patients not
actively being treated with chemotherapy. A long-acting formulation,
darbepoietin, has allowed for dosing every 2 to 3 weeks with these agents,
which is an advantage over the once-a-week schedule most commonly used with
The bisphosphonates, pamidronate and zoledronic acid, are
extensively used in the oncology population to treat or prevent skeletal
related events secondary to a number of malignancies including breast cancer,
multiple myeloma and prostate cancer. See Table 5. They are also considered to
be the drugs of choice for the treatment of hypercalcemia related to
Data was recently presented at the 2008 American Society
of Clinical Oncology (ASCO) meeting in Chicago regarding an improved outcome
for premenopausal women with early breast cancer treated with endocrine
therapy, tamoxifen or anastrozole with goserelin, and zolendronic acid .
Adjuvant bisphosphonate therapy with zoledronic acid was included in two of the
four treatment arms to mitigate the bone loss associated with complete ovarian
suppression and to explore the antitumour effects previously demonstrated in
preclinical trials. Patients were treated with oral tamoxifen and goserelin +/-
zoledronic acid which was compared to oral anastrozole and goserelin +/-
zoledronic acid for 3 years. At least 900 patients were treated with either
tamoxifen or anastrozole. The primary endpoint of the study was disease-free
survival. Secondary endpoints included overall survival and the effects of
treatment on local-regional relapse. At a median follow up of 60 months, the
overall 5-year disease-free survival was 94% and the overall survival was 98.2%
for all patients enrolled. Patients treated with zoledronic acid had an
improved disease-free survival (36% increase) and relapse-free survival (35%
increase) than those patients not treated with the drug. Both findings were
statistically significant. The authors concluded that zoledronic acid
significantly improves clinical outcome beyond those achieved with endocrine
therapy alone. The optimal dose, schedule and duration of therapy with
zoledronic acid in this patient population still need to be established.
Multi-Gene Assays to Predict Recurrence
One of the most exciting advances in the area of cancer
therapy has been the development of multi-gene assays which provide vital
information on patient prognosis and potential response to systemic chemotherapy
which would at least be complementary to the standard pathological and
immunohistochemical techniques currently in use. An example would be the
Oncotype DX� assay . This test is particularly useful in patients with
early stage estrogen receptor (+), lymph node (-) breast cancer. Two hundred
and fifty candidate genes, potentially associated with breast cancer, were
initially selected from the 25,000 genes in the human genome. Three independent
studies and 447 patients were studied to identify a final panel of genes that
strongly correlated with recurrence-free survival. Sixteen genes were selected
based upon these clinical trials along with five reference genes to normalise
the expression of the cancer-related genes. The assay was tested prospectively
to predict the recurrence of disease in tamoxifen-treated, node (-) breast
cancer patients by the National Surgical Adjuvant Breast and Bowel Project
(NSABP) . Reverse-transcriptase-polymerase-chain-reaction (RT-PRC) profiles
were obtained in 675 tumour blocks from patients treated on the NSABP-14 trial.
The results were used to calculate a recurrence score and to determine a risk
group (low, intermediate, high) for each patient studied. Patients were
considered low-risk if the recurrence score was < 18, based upon a total
score of 100, and high-risk with a recurrence score of ≥ 31.
Intermediate-risk was defined as those patients with a recurrence score between
18 and 30. The Kaplan-Meier estimate for the patients in the low-risk group who
were disease-free of distant recurrence at ten years was 93.2%. Patients in the
high-risk group who were free of recurrence at 10 years was significantly less
at 69.5% (p < 0.001). Additional studies such as the prospective
TAILORx Study are presently underway to validate these findings . In this
study, patients will be assigned to one of three treatment groups based upon
their risk of distant recurrence as determined by the OncoType DX� assay.
Patients with an Oncotype DX� recurrence score (ODRS) of < 11 (Group 1) will
receive standard hormonal therapy alone. The drug choice will be at the
discretion of the treating physician. Group 2, ODRS of 11-25 will be stratified
according to tumour size, menopausal status, etc and assigned to either Arm I
(experimental) � patients receiving hormonal therapy as in Group 1 � or Arm II
(standard) � patients receiving standard combination chemotherapy followed by
hormonal therapy as in Group 1. Group 3, ODRS > 25, will receive combination
chemotherapy followed by hormonal therapy as in Group 1. The primary objectives
of the study are to compare the disease-free survival of women with previously
resected axillary lymph node (-) cancer with an ORDS of 11-25 treated with
adjuvant chemotherapy and hormonal therapy versus adjuvant hormonal therapy
alone. The study was also conducted to compare the distant recurrence-free
interval and overall survival in patients with an ODRS of 11-25 treated with
these regimens. Secondary endpoints include determining if adjuvant hormonal
therapy alone is sufficient treatment for patients with ORDS < 11 and determining
their disease-free survival, recurrence-free interval and overall survival. The
results of this trial may dramatically change the way in which women with early
stage ER(+), node (-) breast cancer are treated.
Another microarray available for the evaluation of
patients with early stage breast cancer is the MammaPrint� assay . It is a
70-gene assay which focuses on proliferation, with additional genes associated
with invasion, metastasis, stromal integrity and angiogenesis. Unlike the
OncoType DX� assay, this test requires either fresh frozen tumour samples or
tissues collected into an RNA preservative solution. It is currently offered as
a prognostic test for women under the age of 61 with either estrogen receptor
positive or negative, lymph node negative breast cancer. The test reports
either high- or low-risk patients based upon the results of the assay. A
validation study found the low-risk group having a greater than 90 percent
chance of being disease-free for a minimum of five years .
An abstract reported at the 2007 San Antonio Breast Cancer
Symposium  reported overall survival data at 8 years for patients either
treated or not treated with chemotherapy depending upon their MammaPrint� assay
score. Patients receiving chemotherapy with a good profile (n=39) had an 8-year
overall survival of 95%. This compared with an overall survival of 94% in 57
patients with a good profile that did not receive chemotherapy. Patients with a
poor profile (n=142) had an overall survival of 73% at 8 years. This study
validates the earlier findings proving the utility of the MammaPrint� in this
The potential importance of multi-gene assays such as the
Oncotype DX� assay and MammaPrint� assay adds a new dimension in the attempt to
tailor chemotherapy to the individual patient and treat only those patients who
would truly benefit. Ongoing studies will validate the usefulness of this type
Summary of Advances in Chemotherapy and Supportive Care
The recent advances in the treatment of cancer � targeted
therapy, more effective anti-emetics, the utilisation of growth factors,
emphasis on bone health and the advent of genomic testing � have made it much
easier to treat patients and achieve improved outcomes, making most
malignancies chronic diseases. This trend will continue into the foreseeable
future with over 250 new compounds presently in clinical trial (see Table 6). Targeted
therapy, improved supportive care drugs, and genomic testing all have the
potential to improve the outcomes in patients with various malignancies. There
is, however, significant added cost for these new drugs and technology which
may limit their approval and utilisation in some parts of Asia.
Challenges for Implementation of Advanced Cancer Care in Asia
As with any treatment for cancer, a number of potential
problems need to be addressed. They include, but are not limited to, the
- Access to adequate health care
- The role of alternative medicine
- Availability of newer agents
- Expense of newer agents
- Complexity of prescribed regimen
- Toxicities of therapy and ability to treat them
- Access to supportive care agents
- Knowledge synthesis and transfer
- Palliative and supportive care
Chemotherapy has changed a great deal over the past 20
years. It has gone from an attempt to eradicate all dividing cells with the
hope that normal cells would repair the damage more readily and with greater
success than the malignant cell clones, to a better understanding of the
molecular changes which malignant cells undergo. This improved understanding
has helped in the development of targeted therapy that is more effective and
less toxic. Improved palliative and supportive care have also added to improved
response rates, overall survival and quality of life for patients with the
diagnosis of cancer. Coupled with multi-gene assays which assess a patient�s
risk for relapse, these help to better identify those patients who will benefit
from the administration of these therapies. New drug development, with over 250
compounds in active clinical trials, will also aid in the improved survival of
patients with the diagnosis. The costs of these agents, as well as the
combinations in which they are used, may well dictate the success of our fight
against cancer in the very near future.
Figure 1 Extended-Field IMRT plan for Cervical Cancer. Note color wash radiation distribution and integrated boost treating the pathologically positive pelvic lymph nodes.
Table 1 PET tracers for metabolic imaging.
Table 2 FDA approved targeted therapy for the treatment of cancer in the US
Table 3 New Anti-Emetic Drugs
Table 4 Growth Factor Support
Table 6 Examples of Future Oncology Drug Development
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|Received 16 October 2008; accepted 17 October 2008
Correspondence: Department of Radiation Oncology, University of Pittsburgh Cancer Institute, UPMC Cancer Pavilion, 5150 Centre Avenue, #545, Pittsburgh, PA 15232, United States of America. Tel.: +412.623.6723; Fax: +412.647.1161; E-mail: firstname.lastname@example.org (Dwight E. Heron).
Please cite as: Heron DE, Shogan JE, Mucenski JW,
Innovations in chemotherapy and radiation therapy: Implications and opportunities for the Asia-Pacific Rim, Biomed Imaging Interv J 2008; 4(3):e40