VIEWPOINT
www.nature.com/clinicalpractice/onc
S Hellman is the
A.N. Pritzker
Distinguished
Service Professor
in the Department
of Radiation at
the University of
Chicago, IL, USA.
RR Weichselbaum
is the Daniel K
Ludwig Professor
and Chairman of
Radiation Oncology
and Head of
Molecular Oncology
at the University of
Chicago, IL, USA.
Correspondence
*Department of Radiation
and Cellular Oncology
The University of Chicago
Chicago
IL 60637
USA
s-hellman@uchicago.edu
Received 15 November 2004
Accepted 16 December 2004
www.nature.com/clinicalpractice
doi:10.1038/ncponc0075
60 NATURE CLINICAL PRACTICE ONCOLOGY
NCPO-2004-060.indd 60
Importance of local control in an era
of systemic therapy
Samuel Hellman* and Ralph R Weichselbaum
Abundant laboratory and clinical research
suggests that carcinogenesis is a multi-step
genetic process resulting from mutations, which
produce the malignant phenotype. The capaci-
ties for unlimited proliferation either from loss of
senescence or apoptotic potential, and increased
angiogenesis, invasion, and distant seeding and
growth, are components of tumor progression.
Clinical data support the concept that many steps
characteristic of malignancy occur during the
clinically apparent phase of tumor development.1
Examples of such steps include: in situ tumors
becoming invasive; the occurrence of micro-
metastases without angiogenesis; increases in
tumor size, recurrence or progression correlated
with an increase in histologic grade; increases in
tumor size or progression related to increased
metastatic likelihood; and mutations in the
genes expressing p53,2 E-cadherin,3 nm234 and
loss of function of other genes associated with
a poor prognosis. Clinically apparent cancer is
best described as a spectrum or continuum of
malignant capacities that result from tumor
progression by evolutionary means.5,6
Currently cancer is being diagnosed earlier,
when there is relatively less malignant potential.
This is exemplified by the increase in the diag-
nosis of in situ and early-stage cancers as a result
of improved screening methods and increased
public awareness. The current presentation
of breast cancer in the US is unlike that seen
by Halsted when he described the centrifugal
orderly spread of cancer and the resultant
therapeutic strategy of en bloc resection. The
series described by Halsted comprised patients
with locally advanced primary breast cancers,
the majority of whom had clinically involved
axillary lymph nodes. In contrast, currently
more than half of the breast cancer cases
seen in the US are either intraductal or stage
I tumors. There is also a revolution in tumor
imaging that has resulted in better delineation
of the primary lesion and earlier detection of
metastases. Improved tumor diagnosis has
caused significant stage migration with more
2005 Nature Publishing Group
homogeneous stages and has identified meta-
stases that were previously undetected or had
a questionable diagnosis. This is an evolving
process, and with PET scanning and molecular
imaging just beginning to be utilized in the
clinic, even earlier detection and further stage
migration can be expected.
Therapy of cancer has also changed in the
past 50 years. With the paradigm of metastatic
proclivity, which is largely predetermined before
clinical appearance, becoming the predominant
model in the last quarter of the 20th century,
systemic adjuvant therapy has become a widely
used and effective form of treatment for a
number of different tumors. Systemic therapy
for overt metastatic disease has also improved
although not cured most tumors, but with a few
remarkable successes such as lymphomas and
testicular cancer. With these changes in tumor
paradigm, diagnosis, stage at presentation and
therapy, what now is the place of local treat-
ment in a curative treatment strategy? Local
control is or may be an important element of
a curative treatment strategy in four instances
in the evolving natural history of cancer: before
tumors metastasize; when combined with adju-
vant chemotherapy for the treatment of occult
metastatic disease; to treat oligometastases, i.e.
metastases limited in number and location;7 and
finally to potentially eradicate residual meta-
static deposits remaining after largely effective
systemic treatment.
Treatment of cancers before they have meta-
stasized is the ideal strategy. Mammography
has reduced breast cancer deaths by ~30% in
women 5070 years old. The explanation for
this must be that the cancers were found before
metastases had disseminated and that metastases
would have occurred if the primary tumors had
not been detected until they were clinically
evident. Screening and early diagnosis have also
been effective in the improvement in survival
of cervix, prostate, and possibly colon and lung
cancers. There is also an interesting lesson to
be learned from the trials of post-mastectomy
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radiation treatment in breast cancer patients
receiving adjuvant systemic therapy.8,9 This
local treatment improved survival by an absolute
amount similar to that produced by the systemic
treatment. These two treatments, one directed
at eradicating local and regional disease and the
other directed at occult metastatic deposits when
administered in an initial therapeutic program,
improved breast cancer survival by about 20%
(10% from systemic treatment and an additional
10% from effective local therapy.)
Perhaps most exciting is the potential cure of
metastases utilizing local treatment methods.
While it has been well known that oligo-
metastases can be cured in the lung and liver in
2540% of cases, aggressive local treatment of
metastasis has been considered limited to only
a few tumors in somewhat rare circumstances.
Soft tissue and bone sarcomas can be cured by
resection of a limited number of pulmonary
metastases, likewise hepatic metastases can be
resected in some patients with colorectal cancer.
Identification of oligometastases has improved
in terms of determination of their number
and extent and identification of previously
undetected deposits. For example, positron
emission tomography scanning has resulted in
occult metastases being determined in ~20% of
patients with non-small-cell lung cancer.10 If
this and other imaging techniques can identify
occult disease in seemingly early-stage patients
from this and other primary sites, these lesions
often may be oligometastases. Aggressive but
focused local treatment of these lesions may
lead to cancer cures because it will affect patients
destined to fail utilizing the current therapeutic
strategies. There are a number of advances in
surgery and radiation therapy as well as newer
modalities such as radiofrequency ablation and
focused ultrasound tumor destruction. These all
offer the possibility of applying minimal or non-
invasive treatment directed at very small tumor
deposits utilizing imaging guidance. The final
group of patients that may benefit from discrete
treatment of metastatic cancer are those patients
whowhile they may have had widespread
metastases before systemic treatmenthave
only limited discrete foci of tumor amenable
to focal ablation after such therapy. Examples
are currently limited and include residual meta-
stasis in patients with testicular cancer, Wilms
tumor, and small cell lung cancer. This concept
may eventually be applied to patients with stable
disease treated with new targeted therapies, such
FEBRUARY 2005 VOL 2 NO 2
2005 Nature Publishing Group
NCPO-2004-060.indd 61
VIEWPOINT
www.nature.com/clinicalpractice/onc
as anti-angiogenic therapy or kinase inhibitors, Competing interests
in addition to patients treated with conventional The authors declared
they have no competing
chemotherapy and hormonal treatment. An interests.
example might be patients with gastrointestinal
stromal tumors treated with imatinib mesylate.
While this Viewpoint might seem overly opti-
mistic, we believe it to be fair and equally likely
to be too cautious. It is clear is that the pres-
entation of cancer is quite different than that
on which both the Halsted and predeterminist
paradigms are based. A spectrum of disease
proclivities that are the result of tumor progres-
sion, including both contiguous spread as well
as early dissemination but with most tumors
somewhere in between, seems to describe best
the cancer seen today. With current screening
and imaging methods tumors are being
detected earlier in this spectrum. Hopefully,
genetic or proteomic approaches may help
place individual tumors within this continuum.
Emerging diagnostic and molecular imaging
methods as well as new and refined treatments
all augur well for more opportunities for local
therapies to improve tumor cure as a part of a
multi-modality strategy.
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