The paper by Mendenhall et al addresses a very debatable issue,
ie, the influence of nodal stage on local control for head and
neck carcinomas treated by radiotherapy. The paper is well written
and appropriately referenced, and the authors fairly conclude
that, based on currently available data, nodal stage has no clear
impact on the probability of primary local control after radiotherapy.
Why Are the Studies Inconclusive?
It is clear that among the studies cited in this review, only
a few were specifically designed to address this question. These
include one study from the University of Texas M.D. Anderson Cancer
Center (Mendehall et al's reference 16), which showed a positive
correlation, and two studies from the University of Florida (their
references 1 and 2), which showed the opposite. The studies from
both groups used verified statistical methods to test for this
type of relationship. In the M.D. Anderson study, the site was
limited to the supraglottic larynx, while in the Florida studies,
all sites were considered, and no correlation was found in any
of them. The only significant difference between these studies
was in the method for grading neck disease. The M.D. Anderson
study used an adaptation of the AJCC staging system in the form
of an arbitrary scale from 0 to 9 that incorporated nodal size,
laterality, and number, in an attempt to better reflect the volume
of neck disease.
The issue of nodal classification is a critical one that could
explain, at least in part, the discrepancy among these studies.
Most of the studies that investigated this relationship between
nodal disease and local control have used various staging systems
to categorize the severity of nodal disease. These include nodal
status (node-positive or -negative), different versions of the
AJCC or UICC staging systems, and the level-based Ho's classification
system used in nasopharyngeal carcinoma . It is not intuitively
obvious that node level would have the same biologic meaning as
node volume or number with respect to the end point of local control
at the primary site.
It is also important to recognize that some other factors not
accounted for in retrospective studies could have acted as confounding
variables and contributed to this inconsistency. Such factors
include possible variations in treatment prescription, techniques,
and other parameters that could have been influenced by the existence
or nonexistence of neck disease. In this type of retrospective
analysis, these inherent uncertainties could actually confound
and overshadow the significance of a given parameter or, conversely,
contribute erroneously to its selection as a surrogate for an
The biologic interpretations of a possible relationship between
the extent of nodal disease and primary local control are mainly
extrapolated from studies on tumor aggressiveness and related
characteristics; namely, metastatic potential, radioresistance,
and clonogenic cell content. Although the concept of tumor progression
and acquisition of a radioresistant phenotype in metastatic deposits
has been biologically demonstrated in human tumors , the reverse
of this equation (ie, radioresistant tumors are more metastatic)
has not been proven. Recent laboratory studies do not indicate
that radioresistant tumors have higher metastatic potential. Allam
et al recently showed that the metastatic potential of 21 human
and murine cell lines does not correlate with their intrinsic
radiosensitivity , while Thomas et al found that tumor clones
that exhibit high metastatic potential are actually more radiosensitive
rather than radioresistant .
The influence of clonogenic cell content has been studied by Johnson
et al using tumor volume estimates of primary and nodal disease
derived from CT . The authors showed a clear, strong correlation
between total tumor volume (primary and nodal) and treatment response.
Unfortunately, they used a global approach that combined the primary
and nodal tumor volume for comparison with the composite end point
of both local and regional failure. Because, in several instances,
the nodal volume could not be disassociated from the primary tumor
volume on the CT images, the separate influence of nodal volume
on primary tumor response could not be presented .
Possible Role of Cell Kinetics
It has been also postulated that cell kinetics may play a role
in the relationship between nodal stage and the probability of
primary tumor control. In this instance, primary tumors with high
proliferation potential would be less radiosensitive and would
have a higher propensity to metastasize. While the latter has
been documented, the former remains unproven.
Studies on cell kinetics have shown that tumors with high labeling
indices, or high S-phase fractions, have a higher rate of nodal
and distant spread [6,7]. However, studies on the relationship
between cell proliferation and local tumor control after definitive
radiation therapy have clearly indicated that when appropriate
fractionation regimens are used, cell proliferation parameters
do not influence the probability of local control  (also see
Mendenhall et al's reference 8). Moreover, a recent laboratory
study by Pekkola-Heino et al revealed no correlation between proliferation
kinetics and radiosensitivity in 30 newly established squamous
carcinoma cell lines derived from patients with head and neck
cancers . This further indicates that although parameters of
cell proliferation and kinetics are associated with the degree
of tumor aggressiveness, they do not directly correlate with the
inherent radiosensitivity of tumor cells and their response to
In the clinical decision-making process, several factors are incorporated
to optimize treatment schedules and, ultimately, the outcome of
cancer patients. Many clinical prognostic factors are well established
in head and neck cancer (eg, tumor volume and size, site, morphology,
and degree and mode of primary site invasion) and are included
in the process of selecting a treatment or a combination of various
treatment modalities. Other factors are thought to be of significance
but do not have universal acceptance. These include age, gender,
histologic differentiation, involvement of specific sites or structures,
tumor oxygenation, clonogen cell content, cell kinetics, inherent
radiosensitivity, and specific gene expression. Host immune status
has also been implicated in the outcome of patients with head
and neck cancer, but conclusive evidence is lacking [10-13]. Although
some of these factors may turn out to be very useful in the future,
most are not currently considered in the clinic, particularly
those related to the biologic characteristics of the tumor.
In the particular case of nodal stage vs local control, the prognostic
value of this relationship is really weakened by both the discrepancy
in the results of clinical studies and the lack of strong biologic
plausibility and support. From a clinical perspective, the existing
clinical data indicate that selection of therapy in the presence
of nodal disease does not adversely affect local or neck control
if optimal approaches are used [14-16]. Therefore, we agree with
the authors' statement that therapy to the primary site should
not be formulated on the basis of nodal stage or status.
In summary, in light of currently available data, the relationship
between nodal stage and primary local control in head and neck
cancer treated by definitive radiation has not yet been clearly
established, and the authors' conclusion clearly reflects this
point. Although difficult to perform, clinical studies have not
clearly demonstrated the existence of such a relationship, and
recent laboratory data do not provide biologic credence for this
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