Head and Neck Cancer. Emerging Perspectives

585 Pages·2003·21.553 MB·English

by  John F. Ensley, J. Silvio Gutkind, John R. Jacobs and Scott M. Lippman (Eds.)

Contributors
Numbers in parentheses indicate the pages on which the Janet Dancy (535) Cancer Treatment Evaluation Program,
authors' contributions begin. National Cancer Institute, National Institutes of Health,
Bethesda, Maryland 20892
David J. Adelstein (461) Department of Hematology and
Medical Oncology, Cleveland Clinic Foundation, R. Kim Davis (359) Division of Otolaryngology--Head
Cleveland, Ohio 44195 and Neck Surgery, University of Utah School of
Medicine, Salt Lake City, Utah 84132
Muhyi AI Sarraf (491) Department of Radiation Oncology,
Eastern Virginia Medical School, Norfolk, Virginia 23507 John .F Ensley ,3( ,9 167) Department of Medicine,
Oncology, and OtolaryngologymHead and Neck
Panomwat Amornphimoltham (509) Oral and Pharyngeal Surgery, Karmanos Cancer Institute, Wayne State
Cancer Branch, National Institute of Dental and University, Detroit, Michigan 48201
Craniofacial Research, National Institutes of Health,
J. K. Field (117) Molecular Genetics and Oncology Group,
Bethesda, Maryland 20892
Clinical Dental Sciences, University of Liverpool and
K. Klan Ang (445) Department of Radiation Oncology, Roy Castle International Centre for Lung Cancer
The University of Texas M.D. Anderson Cancer Center, Research, Liverpool L69 3BX, United Kingdom
Houston, Texas 77030
Arlene A. Forstiere (475) Department of Oncology, Johns
William B. Armstrong (339) Department of Hopkins University School of Medicine, Baltimore,
Otolaryngology--Head and Neck Surgery, University of Maryland 21231
California, Irvine, College of Medicine and Craniofacial/
Maura Gillison (475) Department of Oncology, Johns
Skull Base Surgery Center, University of California,
Hopkins University School of Medicine, Baltimore,
Irvine, Medical Center, Orange, California 92868
Maryland 21231
Thomas H. Bugge (137) Oral and Pharyngeal Cancer
.P G. Shankir Giri (491) Department of Radiation
Branch, National Institute of Dental and Craniofacial
Oncology, Eastern Virginia Medical School, Norfolk,
Research, National Institutes of Health, Bethesda,
Virginia 23507
Maryland 20892
J. Silvio Gutkind (509) Oral and Pharyngeal Cancer
Brenda Cartmel (261) Department of Epidemiology and Branch, National Institute of Dental and Craniofacial
Public Health,Yale University School of Medicine, New Research, National Institutes of Health, Bethesda,
Haven, Connecticut 06520 Maryland 20892
Gary Clayman (555) Department of Surgery, The Walter N. Hittelman (227) Department of Experimental
University of Texas M.D. Anderson Cancer Center, Therapeutics, The University of Texas M.D. Anderson
Houston, Texas 77030 Cancer Center, Houston, Texas 77030
Barbara Conley (535) Cancer Treatment Evaluation John R. Jacobs (329) Department of Otolaryngology--
Program, National Cancer Institute, National Institutes of Head and Neck Surgery, Karmanos Cancer Institute,
Health, Bethesda, Maryland 20892 Wayne State University, Detroit, Michigan 48201
xiii
xiv srotubirtnoC
Fadlo R. Khuri (271) Department of Thoracic/Head and Douglas E. Morse (261) New York University College of
Neck Medical Oncology, The University of Texas M.D. Dentistry, New York, New York 10010
Anderson Cancer Center, Houston, Texas 77030
Jose E. Otero-Garcia (329) Department of Otolaryngologym
Edward S. Kim (271) Department of Thoracic/Head and Head and Neck Surgery, Karmanos Cancer Institute,
Neck Medical Oncology, The University of Texas M.D. Wayne State University, Detroit, Michigan 48201
Anderson Cancer Center, Houston, Texas 77030
Urjeet Patel (433) Department of Otolaryngology,
Harold Kim (9) Department of Radiation Oncology, Washington University, .tS Louis, Missouri 63110
Karmanos Cancer Institute, Wayne State University,
Vyomesh Patel (509) Oral and Pharyngeal Cancer Branch,
Detroit, Michigan 48201
National Institute of Dental and Craniofacial Research,
S. Kim (151) Department of Otolaryngology and National Institutes of Health, Bethesda, Maryland 20892
Communication Sciences, SUNY Upstate Medical
Tomasz Pawlowski (569) Department of Pathology,
University, Syracuse, New York 13210
University of California, Irvine, College of Medicine,
Wayne M. Koch (305,523) Department of Otolaryngologym Orange, California 92868
Head and Neck Surgery, Johns Hopkins University
Jay PiceirUlo (433) Department of Otolaryngology,
School of Medicine, Baltimore, Maryland 21286
Washington University, .tS Louis, Missouri 63110
Randall H. Kramer (65) Oral Cancer CentermDepartment
Catherine Poh (245) School of Kinesiology, Simon Fraser
of Stomatology, School of Dentistry, University of
University, Burnaby, British Columbia, Canada V5A 6S1
California, San Francisco, San Francisco, California
and Faculty of Dentistry, University of British Columbia,
94143
Vancouver, British Columbia, Canada V6T 3Z1
Omer Kucuk (201) Karmanos Cancer Institute, Wayne
Ananda Prasad (201) Karmanos Cancer Institute, Wayne
State University, Detroit, Michigan 48201
State University, Detroit, Michigan 48201
Stephen .Y Lai (405) Department of Otolaryngology~ K. Thomas Robbins (393) Department of Otolaryngologym
Head and Neck Surgery, University of Pennsylvania Head and Neck Surgery, University of Florida,
Medical Center, Philadelphia, Pennsylvania 19104 Gainesville, Florida
J. Jack Lee (287) Department of Biostatistics, The Miriam R. Rosin (245) British Columbia Cancer
University of Texas M.D. Anderson Cancer Center, Agency/Cancer Research Centre, Vancouver, British
Houston, Tesax 77030 Columbia, Canada V5Z 4E6 and School of Kinesiology,
Simon Fraser University, Burnaby, British Columbia,
Chidchanok Leethanakul (509) Oral and Pharyngeal
Canada V5A 1 $6
Cancer Branch, National Institute of Dental and
Craniofacial Research, National Institutes of Health, A. Rustgi (57) Laboratory of Molecular Pathology, Harvard
Bethesda, Maryland 20892 University, School of Dental Medicine, Boston,
Massachusetts 02115
Caryn Lerman (185) University of Pennsylvania Health
Sciences, Philadelphia, Pennsylvania 19104 .W Sakr (35) Department of Pathology, Wayne State
University, School of Medicine, Detroit, Michigan 48201
.F Lonardo (35) Department of Pathology, Wayne State
University, School of Medicine, Detroit, Michigan 48201 Naomi R. Schechter (445) Department of Radiation
Oncology, The University of Texas M.D. Anderson
Val J. Lowe (23) Department of Radiology, Mayo Clinic
Cancer Center, Houston, Texas 77030
and Foundation, Rochester, Minnesota 55905
Robert A. Schnoll (185) Fox Chase Cancer Center,
Lawrence G. Lum (569) Roger Williams Cancer Center,
Cheltenham, Pennsylvania 19012
Providence, Rhode Island 02908
Crispian Scully (117) Eastman Dental Institute for Oral
Z. Maciorowski (167) Institut Curie, Paris 75005, France
Health Care Sciences, University College London,
Susan .T Mayne (261) Department of Epidemiology and University of London, London WC1X 8LD, United
Public Health,Yale University School of Medicine, New Kingdom
Haven, Connecticut 06520
Adrian M. Senderowicz (535) Molecular Therapeutics
Jesus E. Medina (317) Department of Otorhinolaryngology, Unit, Oral and Pharyngeal Cancer Branch, National
The University of Oklahoma Health Sciences Center, Institute of Dental and Craniofacial Research, National
Oklahoma City, Oklahoma 43190 Institutes of Health, Bethesda, Maryland 20892
srotubirtnoC VX
Terry Y. Shibuya (339, 569) Department of Carter Van Waes (535) National Institute of Deafness and
Otolaryngology--Head and Neck Surgery and the Chao Communication Disorders, National Institutes of Health,
Family Comprehensive Cancer Center, University of Bethesda, Maryland 20892
California, Irvine, College of Medicine and
Robert E. Watson, Jr. (23) Department of Radiology, Mayo
Craniofacial/Skull Base Surgery Center, University of
Clinic and Foundation, Rochester, Minnesota 55905
California, Irvine, Medical Center, Orange, California
92868 Randal S. Weber (405) Department of Otolaryngology~
Head and Neck Surgery, University of Pennsylvania
Peter Shields (213) Cancer Genetics and Epidemiology
Medical Center, Philadelphia, Pennsylvania 19104
Program, Lombardi Cancer Center, Georgetown
University Medical Center, Washington, DC 2007 Qingyi Wei (213) Department of Epidemiology, The
University of Texas M.D. Anderson Cancer Center,
E.J. Shillitoe (151) Department of Microbiology and
Houston, Texas 77030
Immunology, SUNY Upstate Medical University,
Syracuse, New York 13210 Gregory S. Weinstein (375) Department of Otolaryngology~
Head and Neck Surgery, The Center of Head and Neck
G. Shklar (57) Laboratory of Molecular Pathology, Harvard
Cancer, The University of Pennsylvania Medical Center,
University, School of Dental Medicine, Boston,
Philadelphia, Pennsylvania 19104
Massachusetts 02115
Jack Shohet (339) Department of OtolaryngologymHead Anton Wellstein (81) Lombardi Cancer Center,
Georgetown University, Washington, DC 20007
and Neck Surgery, University of California, Irvine,
College of Medicine and Craniofacial/Skull Base Surgery
Theresa L. Whiteside (569) Departments of
Center, University of California, Irvine, Medical Center,
OtolaryngologymHead and Neck Surgery and Pathology,
Orange, California 92868
Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 31251
David Sidransky (305) Department of Otolaryngology~
D. .T Wong (57) Laboratory of Molecular Pathology,
Head and Neck Surgery, Johns Hopkins University
Harvard University, School of Dental Medicine, Boston,
School of Medicine, Baltimore, Maryland 21286
Massachusetts 02115
Margaret R. Spitz (213) Department of Epidemiology, The
Katharine H. Wrighton (101) Molecular Carcinogenesis
University of Texas M.D. Anderson Cancer Center,
Group, Head and Neck Cancer Program, Guy's King's and
Houston, Texas 77030
.tS Thomas' Schools of Medicine and Dentistry, King's
Brendan C. Stack, Jr. (23) Department of College London, London 1ES 9RT, United Kingdom
OtolaryngologymHead and Neck Cancer, Pennsylvania
.W Andrew Yeudall (101) Molecular Carcinogenesis Group,
State University, College of Medicine, Hershey,
Head and Neck Cancer Program, Guy's King's and
Pennsylvania
.tS Thomas' Schools of Medicine and Dentistry, King's
Erich M. Sturgis (213) Department of Epidemiology, The College London, London 1ES 9RT, United Kingdom
University of Texas M.D. Anderson Cancer Center,
George H. ooY (329, 555) Department of Otolaryngology--
Houston, Texas 77030
Head and Neck Surgery, Karmanos Cancer Institute,
Hideki Tanzawa (117) Department of Oral Surgery, Chiba Wayne State University, Detroit, Michigan 48201
University, Chiba 260-8670, Japan
Lewei Zhang (245) Faculty of Dentistry, University of
Elena Tassi (81) Lombardi Cancer Center, Georgetown British Columbia, Vancouver, British Columbia, Canada
University, Washington, DC 20007 V6T 3Z1
R. Todd (57) Laboratory of Molecular Pathology, Harvard Barry L. Ziober (65) Department of Otorhinolaryngology--
University, School of Dental Medicine, Boston, Head and Neck Surgery, University of Pennsylvania,
Massachusetts 02115 Philadelphia, Pennsylvania 19104
Foreword
You hold in your hands an important new volume detailing You will find here a highly comprehensive review of the
the most advanced, cutting-edge research that is changing state-of-the-art clinical, basic, and translational research in
the way we diagnose, treat, and prevent head and neck this area, with contributions from some of today's most
cancer. These cancers are among the leading cause of death esteemed head and neck cancer scientists. I recommend that
from cancer worldwide, and the survival rate has stubbornly it is worthwhile to purchase it, read it, and keep it on your
refused to change to any significant degree. However, new bookshelf for frequent reference. It's a guide to the most
approaches are finally beginning to offer realistic hope for effective, cutting-edge treatments available today, and a map
improvement in these patients' survival rates and in their to the future of head and neck cancermto the prevention, early
quality of life. detection, diagnosis, treatment, and survival of our patients.
Waun Ki Hong, M.D.
Head, Division of Cancer Medicine
Chair, Department of Thoracic/Head and
Neck Medical Oncology
M. D. Anderson Cancer Center
llVX ~176
C H A P T E R
1
Clinical Perspectives in
Head and Neck Cancer
JOHN F. ENSLEY
Department of Medicine,
Oncology, and Otolaryngology--Head and Neck Surgery
Karmanos Cancer Institute
Wayne State University
Detroit, Michigan 48201
I. Clinical Patterns in Head and Neck Cancer molecular genetic mechanisms involved. The potential value
.A TNM Differences 3 of these clinical observations for translational and basic can-
.B Histopathology Differences 4 cer research is underappreciated and clearly underutilized. In
.C Treatment Outcome Differences 4
the past, justified limitations on experimental research in
.D Correlative Parameters and Outcome 5
humans may have precluded such a direct study of these dis-
II. Human Cancer Surrogates and Models 5
eases 2. However, with today's sophisticated, relatively non-
III. Translational or Correlative Cancer Research
invasive sampling procedures and a patient population that is
IV. Conclusion 6
usually willing to participate, cancer research can and should
References 7
move closer to the direct study of these diseases rather than
using nonrepresentative surrogates and nonvalidated models.
The following are a few illustrative examples, many of which
will be addressed more thoroughly in the chapters in this text.
At first glance, head and neck cancers appear to be a
heterogeneous group of tumors consisting of multiple
histopathologies, primary sites, TNM stages, natural histo-
I. CLINICAL PATTERNS IN
ries, and treatment outcomes 1. However, as one gains clin-
HEAD AND NECK CANCER
ical experience with these cancers, predictable and stable
groupings, with recognizable patterns of tumor/host behavior,
A. TNM Differences
emerge. For example, approximately 70% of patients with
stage T2N0 squamous cell carcinomas (SCC) of the endolar- What factors determine the TNM stage of a patient's
ynx are cured when treated with full course, conventionally tumor when they present with their head and neck cancers?
administered, radiation therapy and 30% are not. Such obser- Certainly time can be implicated in accounting for such
vations suggest that there are fundamental differences in the differences. Patient delay in seeking treatment and their dif-
mechanisms that control the phenotypic expression of these ferences in tolerance thresholds for noxious symptoms are
tumor subgroups and that these differences are not evident at clearly important in this respect. Moreover, certain primary
the time the disease is diagnosed. Because these variations in sites, such as the endolarynx, tend to be detected earlier due
the natural history and treatment outcome certainly result to their anatomy and the subsequent early disruption of func-
from differences in underlying pathophysiological mecha- tion, whereas tumors such as pyriform sinus, supraglottic lar-
nisms, they provide a unique and identifiable opportunity for ynx, and base of tongue tend to present at a later stage. Time
experimental investigation. Unfortunately, such clinical alone, however, does not adequately account for the spectrum
observations rarely become the basis for experimental study, of TNM stages observed at presentation. The inexperienced
and when they do, they are rarely performed with the rigor clinician is often skeptical when confronted with a patient
and thoroughness required to shed light on the underlying who claims that their N3 neck mass was not present a few
Copyright 2003, Elsevier Science (USA).
daeH dna kceN recnaC All rights reserved.
4 .i Introduction
weeks ago, but such skepticism dissipates rapidly when an predictive of the natural or treatment outcome for patients
N1 neck node is actually observed to progress to the N3 stage with SCCHN 9. However, local tumor-host features, such as
in a week following diagnosis. The degree and rate at which tumor-stromal borders, pattern of invasion, degree of stromal
a tumor progresses are determined mainly by molecular- or inflammatory response, access to microvasculature, or vas-
genetic factors that control the (1) rate of local growth and cularity (angiogenesis) and extracapsular lymph node involve-
invasion, which involves the induction of angiogenesis and ment 10,11, have been shown to have a marked effect on the
adequate stromal substructure formation; (2) ability of the ability to achieve and determine negative margins at surgery
cancer cells to migrate to and access local vasculature (motil- and the subsequent rates of local relapse and cure. The subse-
ity and diapedesis); and (3) ability of cancer cells to survive quent local recurrence rates are two to three times higher
in and exit the vasculature and implant at distant sites, which for patients in surgical series who present with histological
also involves the successful induction of angiogenesis and "high-risk" histological phenotypes, and the survival is only
adequate stromal substructure formation at the distant site. one-third to one-half as good as those that do not have such
During this process, to be successful, tumors must deploy features 12,13. However, conventional grading is extremely
or develop mechanisms to suppress the local and systemic significant for salivary gland tumors, such as adenocarcino-
host immune systems. At one end of this spectrum are the mas and mucoepidermoid carcinomas, where high-grade or
unresectable, massive "T4" cancers that invade through mul- poorly differentiated lesions commonly recur very often with
tiple local tissue and bony barriers, including complex vas- distant metastases 14-16. Perhaps the most intriguing tumor
culature, but do not, or cannot, develop regional or distant among all human cancers is the subset of salivary gland
metastatic disease 1 . At the other end are patients with SCC tumors with adenoidcystic histopathology 17. It is common
of unknown primary. In these instances, cells, which, by def- for these tumors to either present with or later evolve distant
inition, do not or cannot propagate or invade sufficiently lung, bone, and liver metastases. Distant metastases may
to be detected at their site of origin, can and do access local remain undetected clinically for years or even decades.
vasculature, disseminate, implant, and often progress vigor- Occasionally, these metastases, once documented, may persist
ously at regional and distant sites 3. Implications for the for decades, with minimal morbidity to the host. How these
inherent biological differences between these two well- cancers and their host remain in such a symbiosis for decades
recognized tumor groups, and the potential they provide for is unclear and unique in cancer. The unique biological aspects
studying cancer mechanisms, are extraordinary. of these tumors and their host-tumor relationships have not
Other examples, illustrative of observations that raise been the subjects of adequate scientific investigation.
similar opportunities for investigation, include the difference
in the rate of distant metastases, which are a feature at pres-
C. Treatment Outcome Differences
entation or recurrence in SCC of the nasopharynx, as opposed
to other squamous cell carcinomas of the head and neck Why do subsets of patients with tumors in seemingly
(SCCHN) 4, the relatively high distant metastatic rate for homogeneous clinical subgroups behave so differently fol-
paranasal sinus carcinomas 5, and, most recently, the site- lowing treatment? This is true regardless of which modality
specific difference in the rate and type of the secondary upper is chosen as the initial therapy. The ability to achieve micro-
aerodigestive tract, which can be associated with the site of the scopically negative surgical margins is possible in nearly
original primary tumor 6. Finally, the clinical implications, 100% of early staged SCCHN and the majority of patients
particularly the risk of distant metastases, for local/regional with advanced, resectable tumors 7. Although microscopi-
lymph node involvement in SCCHN are substantially different cally negative surgical margins remain the hallmark of suc-
when compared with other carcinomas, such as breast, lung, cessful surgery, when achieved, substantial percentages of
prostate, melanoma, and colon. Even with advanced N2C and patients still fail locally with increasing frequency as the
N3 lymph node status, a substantial proportion of these TNM stage increases 1,7. Although this observation has
patients can still be cured with local modalities alone 7. Are been made repeatedly for decades, it is only recently that
these lymph nodes in this region more efficient as "traps" or is studies have demonstrated that negative histological margins
it that the biology of SCCHN itself is different? Does this are not negative "molecular margins" and that histologically
explain the relatively good outcome for patients with SCCHN normal-appearing tissue may be molecularly/genetically
of unknown primary as compared to other types of unknown fated to become malignant or may be malignantly trans-
primaries, such as adenocarcinomas or nonhead and neck formed already 18.
SCC of unknown primary 8? Similar examples can be provided for patients treated
initially with radiation therapy. Clearly, tumor oxygenation
and whether there is an intact mechanism for programmed
.B Histopathology Differences
cell death following lethal radiation are keys to the suc-
The microscopic appearance of the tumor, as described cess or failure when radiotherapy is employed 19,20.
by the conventional morphological grade, is not particularly However, these two factors alone cannot account for the
.1 Clinical Perspectives 5
broad differences in treatment outcome seen in early staged, few instances where newer parameters, such as p53 muta-
T1 and T2 ON tumors. tion or functional status, have been evaluated more exten-
The emergence of chemotherapy as the primary treat- sively, conflicting results have been published 36-38.
ment for patients with SCCHN, first in recurrent tumors 12 , These conflicting results raise another concern about valida-
then in advanced, unresectable disease 22, and now in tion of another sort; i.e., tumor preparative and experimental
organ preservation strategies 23,24, has also produced out- technique methodology validation, which is required before
come subgroups that are not evident before treatment. Even routine research with new parameters and technologies is
with the best regimens, 10-20% of previously untreated performed 39-41 . This is rarely if ever done and accounts
SCCHN patients will not respond or actually progress on for the considerable "noise" in the literature concerning the
treatment, 50% will not achieve a complete clinical remis- clinical value of such correlative research.
sion, and no more than 25-30% have histologically negative
cytotoxic responses. Each of these subgroups, defined by
treatment outcome, has dramatically different survival char-
I!. HUMAN CANCER SURROGATES
acteristics 25,26. It is also clear from organ preservation
AND MODELS
strategies that substantial differences in clinical complete
response rates are specific for the primary tumor site 24,25.
Experimental models are employed in scientific research
As the current treatment for patients with advanced
as substitutes for the subject or object of the research when
SCCHN is often multimodality, it is becoming more difficult
such subjects are not available or cannot be used. To the
to sort out these patterns of failure, and some of these sub-
extent that such models do not represent the subjects or phe-
groups tend to blur or disappear. For example, organ preser-
nomenon under investigation, the research conclusions suf-
vation approaches have been developed on the principle that
fer proportionately. This is true regardless of how carefully
patients failing to achieve at least a partial clinical response
the work is done or how sophisticated the technology uti-
with induction chemotherapy can only be salvaged with sur-
lized. Laboratory models employed to investigate human
gery 27,28. However, the use of sequential concurrent
cancers are of three major types.
chemo/radiation following induction therapy has changed
this algorithm 29. Finally, and most importantly, regardless .1 In vitro and in vivo, nonhuman (usually murine) sys-
of which modality is used initially, it is not clear that the tems. These models exist as either in vivo nonhuman cell
same subpopulation of patients are cured with each modality. lines or tissue models 42-45. These tumors are almost
If indeed they are different populations, as some correlative always induced in syngeneic animals rather than sponta-
studies have suggested 30,31, how are they different and to neously occurring and, other than microscopic appearance,
what extent? This has important implications for individual- bare little clinical resemblance to their human counterparts.
izing patient therapy, increasing the overall cure rates for The use of syngeneic animals, inbred for decades, further
patients with SCCHN, and understanding the underlying distances these models from the genetic heterogeneity and
mechanisms that regulate the behavior of these tumors. complexity with which human tumors arise.
2. More recently, cell lines derived from human cancers
have become models for human cancer 46,47. They suffer
D. Correlative Parameters and Outcome
from the same limitations as any cell line in that most human
Few, if any, correlative parameters have been tested thor- cancers, except for leukemia, are tissues with all the inher-
oughly and adequately enough in SCCHN clinical trials to be ent additional complexities inherent in tissues, organs, and
considered validated and prospectively useful 30,31. Most organisms. Often these lines are passaged for decades (MCF
correlative studies are single institution trials, which, more 7, HeLa cells). More recently, three-dimensional human
often than not, produce conflicting results. In SCCHN, the tumor models (organotypic or raft cultures) derived from
most commonly studied correlative laboratory parameter has human tumors have been developed 48,49. Although they
been DNA content (DNA ploidy and %S phase fraction), are derived from human cancers and often have similar
most often determined by flow cytometry. These parameters appearances, they may not represent human tumors any bet-
have undergone large numbers of single institutional investi- ter than other models, particularly because the important
gations over a period of decades and, most recently, validation tumor-host interaction is still missing.
at the cooperative and intergroup phase III level 30,31. Other 3. Often human tumor cell lines are transplanted into
experimental parameters, including p53, epidermal growth immune-suppressed murine systems in an attempt to simu-
factor (EGF), chromosomal polysomy, loss of heterozygosity late an in vivo system 50,51, but again, these models are
at 3p or 9p, C-erbB2 expression, Ki67 expression, tumor orders of magnitude removed from the spontaneously occur-
angiogenesis, cell cycle (cyclin pathway) regulatory aberra- ring cancers arising in the genetically heterogeneous and
tions, and integrity of apoptotic pathways, have only been immunocompetent human population. However, because
studied anecdotally in small, preliminary trials 32-35. In the they are derived from human cancers, grow as tissues, have
6 .i Introduction
three dimensions, and interact with an intact organism, it is method 56-58. Its components include (1) an observa-
at least possible to compare some features with human tion, (2) the generation of a hypothesis to be tested based
tumors in vivo for model validation such as histopathology, on the observation, (3) the development and validation of
local regional invasion, and metastatic potential. an experimental design and methodology to test the
hypothesis, (4) the conduct of the experiment, (5) data
A potential, but unused, resource for experimental and
gathering and analysis, and (6) conclusions derived from
clinical cancer research exists in spontaneously occurring
data regarding the hypothesis, which is relevant to the
cancers in household or domesticated animals 52. Indeed,
observation.
in this population, which numbers in the millions, sponta-
This is basically a unidirectional system and one that
neous cancers occur at approximately the same rate as in the
works best when not begun in the middle or run back-
humans. Unfortunately, the more common cancers, with the
ward! The observational step of the scientific method is,
exception of canine breast cancer, occur with much less fre-
and has usually been, the critical starting point for most
quency than in humans (lung, prostate, and gastrointestinal).
clinically relevant medical research. It is always the anvil
This is an untapped potential resource for studying sponta-
on which any and all conclusions must ultimately be tested
neously arising cancers in more genetically diverse and less
56. Without this component, data derived from labo-
inbred animals.
ratory experiments "dangle" without meaningful context.
This leads to the most important aspect of model use in
Unfortunately, much, if not most, experimental cancer
experimental research. As stated previously, model use
research currently falls into this category. It seems intu-
should be restricted to those instances in which the actual
itive that when the goal of an investigation is the study of
subject of the experiment is not available or cannot be used.
human cancer, human cancer must be included somewhere
Given the current state of human correlative research, it is
in the process 2. While it is becoming fairly common for
becoming increasingly difficult to argue that such subjects
clinical cancer scientists to spend substantial portions of
are not available. When and if it is proposed that models must
their training time in gaining experimental laboratory
substitute for the subject under investigation, it is imperative
experience, it is still quite rare for basic cancer scientists
that the models be validated before their use. In laboratory
to spend comparable periods during their training learning
cancer research, cancer models are rarely validated and,
about human cancer in the clinic. Clinical observations
more importantly, attempts to validate them are never under-
provide the scaffolding on which laboratory data can be
taken; i.e., attempts must be made to determine with what
organized in a meaningful manner. As the eminent cancer
fidelity these models represent the spectrum of natural history
researcher Van Rensselaer Potter opined over a decade
and biology seen in a particular human cancer. Humbling
ago as he anticipated the emerging human molecular-
reminders of these differences have come from experiences
genetic revolution, "...the assumption that the total
such as during the "stem cell assay" era 53 where investi-
sequencing of the normal human genome will tell us how
gators often found it impossible to grow a human cancer line
life is organized can only lead to a technologic blitzkrieg
in vitro while, simultaneously, finding it impossible to stop
that will produce more descriptive data than the comput-
its growth in the human host from which it was derived!
erized human mind can organize into a blueprint for life--
unless some cybernetics system...is used as a scaffolding"
.111 TRANSLATIONAL OR CORRELATIVE 59,60. Therefore, the "closing of the loop" of the scien-
CANCER RESEARCH tific method, if you will, can and should be practiced as
religiously as possible in experimental cancer research.
The terms translational or correlative research are meant
to represent that area of cancer research that brings together
clinical observations, laboratory research, and the applica- IV. CONCLUSION
tion of the product of this interaction for the treatment of
patients with cancer 54. This process also implies the It is highly unlikely that models that faithfully represent
potential to individualize treatment strategies that are the broad spectrum of biology seen in human cancers, in its
tailored to the patient's tumor biology 55. However, entirety, will ever be created. This will certainly be unlikely for
where is the optimum point, if any, to initiate this process? as long as the observational background required for their
While important and valid molecular-genetic observations development, which can be provided only by the clinical
are often made at cellular and subcellular levels in the knowledge of the spectrum and diversity of these diseases, is
laboratory, how such observations become properly inte- lacking in the formulation and validation of such models. It is
grated into the extraordinary complex panorama of human therefore imperative that basic researchers and clinicians
cancer is often problematic. Guidelines for research that involved in human cancer research work closely in multi-
have evolved over the centuries have culminated in an disciplinary teams. Cross training and continual learning for
agreed upon format generally referred to as the scientific both clinical and basic scientific specialties in a multimodality
.1 Clinical Perspectives 7
environment will be critical for translational strategies to .61 Spiro, R. H., Huvos, A. G., Berk, R, Strong, E. .W (1978). Muco-
reach their full potential. It is also critical that natural exper- epidermoid carcinoma of salivary gland origin. A clinicopathologic
study of 367 cases. Am. .J Surg. 136, 461-468.
iments in human cancer, detected and catalogued by clinical
.71 Spiro, R. H., Huvos, A. G., and Strong, E. .W (1979). Adenoid cystic
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