0360.3016/92 $5.00 + .oO Copjnght 0 1992 Pergamon Press Ltd.

In, J Radrrrrron Oncolr~~y BICI/ Phn Vol. 23. PP. 887-888 Pnnted ,n the U.S.A. All nghts reserved.

??Editorial

THE UNCERTAINTY PRINCIPLE IN CLINICAL DATA LESTER J. PETERS, M.D. Division of Radiotherapy, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030

data, it is often prudent to consider the biologic plausibility of one conclusion versus the other. In the context of the present discussion, one might ask why, on biological grounds, a primary tumor of a given size could be expected to be less radiocurable when associated with nodal metastases. There are at least three possibilities in this regard:

In this issue of the journal, Freeman et al. pose the question, “Does neck stage influence local control in squamous cell carcinomas of the head and neck?’ Their conclusion, based on a careful review of 607 patients with primary carcinomas of the tonsillar region, supraglottic larynx, base of tongue, pharyngeal wall, and soft palate treated by radiotherapy at the University of Florida, is that it does not. This conclusion is the same as that reached in a previous analysis of the University of Florida database (4) but is at variance with several other reports (2, 3, 9, lo), all of which showed inferior primary tumor control rates in patients with nodal metastases disease on presentation. The detailed analysis by Wall et al. ( 10) further demonstrated a direct relationship between the bulk of neck nodal disease and primary tumor control for both early and late T stages; this relationship held regardless of whether or not the neck disease was controlled, although the absolute rate of primary tumor control was lower in those who sustained a neck recurrence. The paper cited by Freeman et al., in support of their own conclusion that no association exists between neck stage and primary tumor control (7) does not, in fact, address the question of radiocurability at the primary site. In attempting to make sense of these conflicting conclusions, one must take into account the generic limitation of retrospective analyses, that is, that unknown prognostic factors may have influenced the results. In addition, as pointed out by Freeman et al., methodological differences in the analyses may have contributed to the different conclusions reached. Another point to remember is that biologic facts are not proved or disproved on the basis of statistical p values. Demonstrating that an observed difference is significant with a < 0.05 means simply that the probability is less than 1 in 20 that the observed difference could have occurred by chance. It does not prove that the difference is real. Conversely, it should never be forgotten that failure to demonstrate a statistically significant dif,ference is not proof that a real d&erence does not exist. In clinical circumstances where there are conflicting

1 Relative radioresistance

and increased metastatic potential could both reflect a higher proportion of clonogenic cells in the primary tumor population. This would increase the likelihood that cells disseminated from the primary tumor would successfully establish metastases in the regional nodes and would also decrease the radiocurability of the primary tumor compared with one of similar size containing fewer clonogenic cells. 2. Common cellular genetic factors may determine both radioresistance and metastatic potential. There is increasing evidence that both the propensity to metastasize and the ability to repair radiation injury are genetically determined (5, 8). Any linkage between the genes controlling for these phenotypes could result in the shared attributes of relative radioresistance and increased metastatic potential. The demonstration by Wall et al. (10) showing a strong correlation between control of disease at both the primary site and in the nodes is consistent with this hypothesis. 3. Tumor cell proliferation kinetics could be expected to affect both primary tumor radiocurability and metastatic potential. Recent preliminary data from the EORTC trial of accelerated fractionation in head and neck cancer have shown that disease-free survival is inversely related to the pretreatment potential doubling time (Tpot) of tumor cells. Furthermore, the probability of local tumor control, at least with standard fractionation, also appears to be reduced for tumors with short Tpot values (1). If we assume that the presence of nodal metastases does, indeed, have a deleterious effect on the probability of con-

Accepted for publication

Reprint requests to: Lester J. Peters, M.D., Division of Radiotherapy (Box 97), UT M. D. Anderson Cancer Center, Houston. TX 77030. 887

1 I May 1992.

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trol of the primary tumor, what are the implications for practicing radiotherapists? First, one must bear in mind the multiplicity of prognostic factors determining radiocurability of head and neck cancers (6). In deciding the best treatment strategy for a given patient, all the available prognostic information as well as the functional consequences of different treatment options need to be taken into account, and undue weight should not be placed on any single factor. Thus, it would be quite wrong to construe the presence of lymph nodal disease, in and of itself, as a reason to recommend alternative treatment modal-

Volume 23.

Number

4. 1992

ities for patients with potentially radiocurable primary tumors. However, there is a practical implication for radiotherapeutic dose prescription. In general, advanced stage head and neck cancers are treated to the limit of tolerance for the site and volume of disease, while earlier stages generally receive a lesser dose. In the light of the available clinical data, it would be prudent to avoid this practice in patients with bulky neck nodal disease and to treat them as if their T stage was higher than in patients with tumors of similar size but having a node-negative neck.

REFERENCES I. Begg, A. C.; Hofland. I.; Van Glabekke, M.: Bartelink. H.: Horiot, J. C. Predictive value of potential doubling time for radiotherapy of head and neck tumor patients: Results from the EORTC Cooperative Trial 2285 1. Sem. Rad. Oncol. 2: 22-25; 1992. 2. Hahn, S. S.; Spaulding, C. A.; Kim, J-A.: Constable. W. C. The prognostic significance of lymph node involvement in pyriform sinus and supraglottic cancers. Int. J. Radiat. Onco]. Biol. Phys. 13:1143-l 147:1987. 3. Harwood, A. R.; Beale, F. A.: Cummings, B. J.; Keane. T. J.; Payne, D. G.; Rider, W. D.; Rawlinson, E.; Elhakim, T. Supraglottic laryngeal carcinoma: An analysis of dosetime-volume factors in 410 patients. Int. J. Radiat. Oncol. Biol. Phys. 9:31 l-319:1983. 4. Mendenhall, W. M.; Parsons, J. T.; Amdur, R. J.; Spangler. A. E.; Williams, T. R.; Cassisi, N. J.: Million, R. R. Squamous cell carcinoma of the head and neck treated with radiation therapy: The impact of neck stage on local control. Int. J. Radiat. Oncol. Biol. Phys. 14:249-252;1988. 5. Nicolson, G. L. Gene expression, cellular diversification and

tumor progression to the metastatic phenotype. BioEssays l3:337-342;199 I. 6. Peters, L. J.; Fletcher, G. H. Causes of failure of radiotherapy in head and neck cancer. Radiother. & Oncol. I :53-63; 1983. 7. Richard, J. M.; Sancho-Garnier, H.; Micheau, C.; Saravane, D.; Cachin, Y. Prognostic factors in cervical lymph node metastasis in upper respiratory and digestive tract carcinomas: Study of 1.7 I3 cases during a 15-year period. Laryngoscope 97:97-lOl;l987. L. H. Properties and applications of human 8. Thompson, DNA repair genes. Mut. Res. 247:2 13-2 19; I99 1. 9. Van den Bogaert, WI.; Ostyn, F.: van der Schueren, E. The different clinical presentation, behaviour and prognosis of carcinomas originating in the epilarynx and the lower supraglottis. Radiother. & Oncol. I : 1 I7- 13 1;1983. IO. Wall, T. J.; Peters, L. J.; Brown, B. W.; Oswald, M. J.; Milas, L. Relationship between lymph nodal status and primary tumor control probability in tumors of the supraglottic larynx. Int. J. Radiat. Oncol. Biol. Phys. 11:1895-1902;1985.

The uncertainty principle in clinical data.

0360.3016/92 $5.00 + .oO Copjnght 0 1992 Pergamon Press Ltd. In, J Radrrrrron Oncolr~~y BICI/ Phn Vol. 23. PP. 887-888 Pnnted ,n the U.S.A. All nghts...
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