EDITORIAL
Oligometastases
CANCER TREATMENT
stated paradigm is based
of disease on an oftenSince
pathogenesis.
1894, when W.S. Halsted"'2 clearly elucidated a mecha-
un-
nism of breast cancer spread and used it to design and
support the radical mastectomy, surgical and radiothera-
peutic approaches to most cancers have been based on this
theory. The Halsted theory proposed that cancer spread is
orderly, extending in a contiguous fashion from the pri-
mary tumor through the lymphatics to the lymph nodes
and then to distant sites. Radical en bloc surgery, such
as radical neck dissection in continuity with removal of
the primary tumor, radical hysterectomy, and primary and
regional irradiation for a variety of tumor sites are all
based on this notion of cancer spread. More recently,
another hypothesis has gained prominence, also first sug-
gested with regard to breast cancer.3 This systemic hy-
pothesis proposes that clinically apparent cancer is a sys-
temic disease. Small tumors are just an early
manifestation of such systemic disease, which, if it is
to metastasize, has already metastasized. Lymph node
involvement is not orderly contiguous extension, but
rather a marker of distant disease. Systemic metastases
are multiple and widespread, and when subclinical are
referred to as micrometastases. Under these circum-
stances, treatment of local or regional disease should not
affect survival.
Both the contiguous and systemic theories of cancer
pathogenesis are too restricting and do not consider what
is now known about tumor progression during clinical
evolution. A third paradigm, one that synthesizes the con-
tiguous-systemic dialectic, has been suggested by one of
us' to explain the natural history of breast cancer. This
thesis argues that cancer comprises a biologic spectrum
extending from a disease that remains localized to one
that is systemic when first detectable but with many inter-
mediate states. Metastases are a function of both tumor
size and tumor progression.
While much tumor evolution occurs during the preclin-
ical period, we suggest that there is a progression of ma-
lignancy during the clinical evolution of a cancer. There
is some evidence to support this progression of clinical
cancer because pathologic grade usually correlates with
tumor size, with smaller tumors being of lower grade than
large ones.7'-0 Although this may be owing in part to
the more rapid growth of high-grade tumors, it is also
consistent with tumor progression during the clinical evo-
lution of the tumor. Such possible tumor progression with
increasing metastatic capacity during the clinically appar-
ent period is receiving increasing support as we learn
8 Journal of Clinical Oncology, Vol 13, No 1 (January), 1995: pp 8-10
more about the multistep nature of the development of
malignancy.1113 Once tumors become invasive, they may
gradually acquire the properties necessary for efficient
and widespread metastatic spread.1 4 Therefore the likeli-
hood, number, and even sites of metastases may reflect
the state of tumor development. This suggests that there
are tumor states intermediate between purely localized
lesions and those widely metastatic. Such clinical circum-
stances are not accounted for by either the contiguous
or the systemic hypotheses. The systemic hypothesis is
binary: metastases either do or do not exist. If present,
even if microscopic, they are extensive and widespread.
The contiguous hypothesis considers systemic metastases
to occur only after nodal disease; but when they occur,
they are also blood borne, extensive, and widespread.
From considerations of these theories of cancer dissem-
ination, in the light of the emerging information on the
multistep nature of cancer progression, we propose the
existence of a clinical significant state of oligometastases.
For certain tumors, the anatomy and physiology may limit
or concentrate these metastases to a single or a limited
number of organs. The likelihood of the oligometastatic
state should correlate with the biology of tumor progres-
sion, rough clinical surrogates of which, for many tumors,
might be primary tumor size and grade. Metastasizing
cells may seed specific organs as a function of the seeding
tumor cell number and characteristics as well as the recep-
tivity of the host organ. The importance of "seed and
soil" have been considered elsewhere 4", 5 and will not be
discussed further. Tumors early in the chain of progres-
sion may have metastases limited in number and location
because the facility for metastatic growth has not been
fully developed and the site for such growth is restricted
(this is in contrast to micrometastases, which, although
small in size, are extensive in number). With further pro-
gression, the tumor seeding efficiency increases and be-
comes less fastidious with regard to the location of meta-
static growth. In addition to this progression of
malignancy, the increasing primary tumor size and there-
fore cell number should also be correlated with the in-
creasing number of cells seeding. Tumor size is the princi-
pal basis of tumor staging and, with histologic grade,
correlates with the likelihood of metastases.6 -106 This,
we suggest, is due to the number of tumor cells, the tumor
vascularity, and malignant progression as tumors grow.
An attractive consequence of the presence of a clini-
cally significant oligometastatic state is that some patients
so affected should be amenable to a curative therapeutic
strategy. The occasional success of surgical excision or
EDITORIAL
radiation ablation of one or a small number of pulmonary,
hepatic, or even brain metastases is evidence of a limited
form of the oligometastatic state. The complete resection
of pulmonary metastases from soft tissue sarcomas, osteo-
sarcomas, and renal cell cancers can be curative even
when they are multiple."7 The likelihood of this for soft
tissue sarcoma is correlated with tumor size and tumor
grade.'" Of 859 hepatic resections for metastatic colo-
rectal cancer, there was a 25% 5-year disease-free sur-
vival.19 Long-term survival decreases with the number of
metastases probably both as a function of the adequacy
of the resection and the increased likelihood of occult
disease. However, recurrences following hepatic resec-
tion are often restricted to the liver and, if amenable to
surgical re-resection, have a likelihood for cure similar
to that seen with the first resection. 20,21 Radiosurgery is
being applied to solitary brain metastases with some ini-
tial success. 22 The limited effectiveness of these treat-
ments of oligometastases has been primarily the result of
an inability to recognize all metastases and the fact that
these seemingly limited lesions were too often a manifes-
tation of undetected widespread cancer. The importance
of oligometastases depends on how commonly they are
present. Only further study will determine this, but the
frequency of their presence in the liver with colorectal
cancer and in the lung with certain sarcomas offers some
evidence of their clinical importance. It is estimated that
of the 30% of cancer patients who develop pulmonary
metastases, one-third have the primary tumor controlled
and the metastases limited to the lung.2 3 Similarly, one
third of all patients with colorectal cancer develop liver
metastases, often as the only site of metastatic disease. 20
Effective treatment of oligometastases will require identi-
fication of all of the lesions and, most importantly, of
the state of intermediate tumor progression likely to be
consistent with the oligometastatic state. This must be
distinguished from the circumstance in which the identi-
fied metastases are the most evident of a much larger
number of widespread deposits. A special form of oligo-
metastases recognized today as amenable to curative re-
gional therapy is limited lymph node involvement, which
is often effectively treated by surgical excision or radia-
tion therapy.
As effective chemotherapy becomes more widely ap-
plicable, there should be another group of patients with
oligometastases. These are patients who had widespread
metastases that were mostly eradicated by systemic
agents, the chemotherapy having failed to destroy those
remaining because of the number of tumor cells, the pres-
ence of drug-resistant cells, or the tumor foci being lo-
cated in some pharmacologically privileged site. Thus,
9
effective chemotherapy may fail to be curative because
of only a few metastases.
The number of metastases should reflect the biologic
progression of the tumor. It will also determine the oppor-
tunities and the nature of potentially therapeutic interven-
tions. Not only is there a spectrum of malignancy, but
there is an accompanying spectrum of potentially curative
treatments. Tumors early in their progression should be
amenable to localized therapy. Patients with oligometas-
tases, either de novo or following systemic treatment,
should be cured by ablation of these lesions. More ad-
vanced disease will require more aggressive and effective
systemic treatment.
Acceptance of this new paradigm for neoplastic patho-
genesis and the resulting clinical relevance of the oligo-
metastastic state requires the use of the most sophisticated
diagnostic and therapeutic techniques. This paradigm em-
phasizes the importance of markers specifically related to
where in the spectrum of malignancy an individual cancer
is located. Truly localized, oligometastatic, and widely
metastatic tumors are likely to require different strategies.
New methods of surgery or radiation therapy may allow
curative treatment of such oligometastases either alone
or combined with systemic therapy. Their effectiveness
will be critically dependent on the specificity, sensitivity,
precision, and accuracy of tumor imaging. The treatment
of these metastases must be equally precise and limit
normal tissue toxicity. New operations for oligometas-
tases should be devised. Such procedures--relying on
the identification of appropriate patients-must excise or
ablate the metastases completely while at the same time
preserving normal function and structure. The likelihood
of complete resection of pulmonary metastases from soft
tissue sarcomas is dependent on histologic subtype, which
suggests that there are differing patterns of metastatic
growth for different primary tumors."' Knowledge of such
patterns of local extension for different metastastic tumors
in different sites will be necessary to any locally applied
therapy of metastases. Conformal radiotherapy now being
investigated for the treatment of primary tumors may find
the treatment of oligometastases its most important appli-
cation. 24 -26 This technique allows both an increase in the
tumor dose and a reduction in normal tissue toxicity by
restricting, as much as possible, the radiation to the accu-
rately imaged tumor while avoiding critical normal tis-
sues. It requires extensive use of computers to integrate
the digital information of the imaging modality to radia-
tion treatment planning and then to deliver precise repro-
ducible computer controlled radiation delivery. Most crit-
ically, the integrated use of local and systemic treatment
modalities requires determining where an individual tu-
10
mor is located within the continuum of malignancy. This
will be the challenge for the newly emerging field of
molecular diagnostics.
The importance of the oligometastatic state will be
dependent on the size of the group of patients for whom
it offers curative prospects. Although the notion of there
being some patients with limited metastases is recog-
nized, it is thought to be quite uncommon. What is im-
portant in oligometastases is the recognition that it is not
just a stochastic oddity, but rather that it is based on a
state of limited metastatic capacity and is a characteristic
of many tumors during their clinical evolution. The explo-
ration of the size and nature of the oligometastatic state
will profit from a careful review of past experience. Anal-
ysis of the site, number, and anatomic characteristics of
REFERENCES
1. Halsted WS: The results of operations for the cure of cancer
of the breast performed at the Johns Hopkins Hospital from June,
1889 to January, 1894. Johns Hopkins Bull 4:297, 1894
2. Halsted WS: The results of radical operations for the cure of
carcinoma of the breast. Ann Surg 46:1, 1907
3. Keynes G: Carcinoma of the breast, the unorthodox view. Proc
Cardiff M Soc 40, 1954
4. Crile G Jr: A Biological Consideration of the Treatment of
Breast Cancer. Springfield, IL, Charles C. Thomas, 1967
5. Fisher B: Laboratory and clinical research in breast cancer--
A personal adventure: The David A Karnovsky Memorial Lecture.
Cancer Res 40:3863-3874, 1980
6. Hellman S: The natural history of small breast cancers: The David
A. Karnovsky Memorial Lecture. J Clin Oncol 12:2229-2234, 1994
7. Peer PGM, Holland R, Hendriks JHCL, et al: Age-specific
effectiveness of the Nijmegen population-based breast cancer-
screening program: Assessment of early indicators of screening ef-
fectiveness. J Natl Cancer Inst 86:436-440, 1994
8. Tabar L, Fagerberg G, Duffy SW, et al: Update of the swedish
two-county program of mammographic screening for breast cancer:
Radiat Clin North Am 30:187-210, 1992
9. Tubiana M, Koscielny S: Natural history of human breast can-
cer: Recent data and clinical implications. Breast Cancer Res Treat
18:125-140, 1991
10. Gleason DF, Melinger GT, Veterans Administration Coopera-
tive Urological Research Group: Prediction of prognosis for prostatic
adenocarcinoma by combined histological grading and clinical stag-
ing. J Urol 111:58-64, 1974
11. Vogelstein B, Kinzler KW: The multistep nature of cancer.
Trends Genet 9:138-141, 1993
12. Rinker-Schaeffer CW, Partin AW, Isaacs WB, et al: Molecu-
lar and cellular changes associated with the acquisition of metastatic
ability by prostatic cancer cells. The Prostate (in press)
13. Schwechheimer K, Cavenee WK: Genetics of cancer predis-
position and progression. Clin Invest 7:488-502, 1993
14. Price JE, Aukerman SL, Fidler IJ: Evidence that the process of
HELLMAN AND WEICHSELBAUM
metastases as a function of primary tumor size, location,
and differentiation, as well as the use of newer molecular
markers on paraffin-imbedded materials, should provide
a great deal of information. Some of this should be avail-
able in surgical, pathologic, and medical imaging archival
materials. Most importantly, while efforts are made to
determine its size, recognition of the existence and impli-
cations of a state of oligometastases is necessary to invite
active clinical investigation of new and potentially cura-
tive therapeutic strategies.
Samuel Hellman
Ralph R. Weichselbaum
The University of Chicago
Chicago, IL
murine melanoma metastasis is sequential and selective and contains
stochastic elements. Cancer Res 46:5172-5178, 1986
15. Paget S: The distribution of secondary growths in cancer of
the breast. Lancet 1:571-573, 1889
16. Koscielny S, Tubiana M, Le MG, et al: Breast cancer: rela-
tionship between the size of the primary tumour and the probability
of metastatic dissemination. Br J Cancer 49:709-715, 1984
17. Kern KA, Pass HI, Roth JA: Surgical treatment of pulmonary
metastases, in Rosenberg SA (ed): Surgical Treatment of Metastatic
Cancer. Philadelphia, PA, Lippincott, 1987, pp 69-100
18. Gadd MA, Casper EF, Woodruff JM, et al: Development and
treatment of pulmonary metastases in adult patients with extremity
soft tissue sarcoma. Ann Surg 218:705-712, 1993
19. Hughes KS, Simon R, Songhorabodi S, et al: Resection of
the liver for colorectal carcinoma metastases: a multi-institutional
study of the indications for resection. Surgery 100:278-284, 1986
20. Hughes KS, Sugarbaker PH: Resection of the liver for meta-
static solid tumors, in Rosenberg SA (ed): Surgical Treatment of
Metastatic Cancer. Philadelphia, PA, Lippincott, 1987, pp 101-125
21. Nordlinger B, Vaillant J-C, Guiguet M, et al: Survival benefit
of repeat liver resections for recurrent colorectal metastases: 143
cases. J Clin Oncol 12:1491-1496, 1994
22. Flickinger JC, Kondziola D, Lunsford LD, et al: A multi-
institutional experience with stereostatic radiosurgery for solitary
brain metastases. Int J Radiat Oncology Biol Phys 28:797-802, 1994
23. van Dongen JA, van Sloten EA: The surgical treatment of
pulmonary metastases. Cancer Treat Rev 5:29-48, 1978
24. Lichtor AS: Three-dimensional conformal radiation therapy:
A testable hypothesis. Int J Radiat Oncol Biol Phys 21:853, 1991
25. Leibel SA, Heimann R, Kutcher GJ, et al: Three-dimensional
conformal radiation therapy in locally advanced carcinoma of the
prostate: Preliminary results of a phase 1 dose escalation study. Int
J Radiat Oncol Biol Phys 28:55-65, 1994
26. Vijayakumar S, Myrianthopoulos LC, Rosenberg I, et al: Optimi-
zation of radical radiotherapy with Beam's eye view techniques for
non-small cell lung cancer. Int J Radiat Oncol Biol Phys 21:779-788,
1991
Copyright of Journal of Clinical Oncology is the property of American Society of Clinical
Oncology and its content may not be copied or emailed to multiple sites or posted to a listserv
without the copyright holder's express written permission. However, users may print,
download, or email articles for individual use.