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 unidentified parameter.
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 radiation therapy.
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 thesis.