Tumori, 86: 53-58, 2000 CELL KINETICS ANALYSIS IN PATIENTS AFFECTED BY SQUAMOUS CELL CARCINOMA OF THE HEAD AND NECK TREATED WITH PRIMARY SURGERY AND ADJUVANT RADIOTHERAPY Renzo corvo", Giovanni Margarino 2 , Giuseppe SanguinetP, Elio Geido 3 , Marco Scala 2 , Paola Mereu 2 , Monica Cavallari\ Salvatore Bonanno\ Giacomo Garaventa 4 , Marco Barblerl", and Walter Giaretti 3 'Reparto di Oncologia Radioterapica. 2Reparto di Oncologia Chirurgica, 3Laboratorio di Citometria-Biofisica, Istituto Nazionale per la Ricerca sui Cancro, Genova; "Reparto di Otorinolaringoiatria, ASL San Martino-Genova; 5Clinica Otorinolaringoiatrica, Universita di Genova, Italy Background: The increasing complexity of management strate- gies for patients with head and neck squamous cell carcino- ma (HN-SCC) calls for the investigation of new objective prog- nostic parameters to subdivide patients according to the tu- mor's biological aggressiveness. Methods: We evaluated in 35 HN-SCC patients the pretreatment cell kinetics parameters and DNA ploidy after in vivo infusion of bromodeoxyuridine and flow cytometric analysis. Patients were treated with radical surgery followed by conventional ra- diation therapy. Locoregional control data are available for follow-up times above five years. Results: We found that the likelihood of locoregional control for patients with rapidly proliferating HN-SCC characterized by a short potential doubling time (Tpot <5 days) was significantly smaller than for HN-SCC patients with slow tumor proliferation (Tpot >5 days). Moreover, when patients were stratified accord- ing to DNA ploidy and Tpot value, we found that the locoregion- al failure rate for rapidly proliferating tumors was significantly higher for diploid HN-SCCsthan for aneuploid HN-SCCs. Conclusion: The present data suggest that patients with re- sectable HN-SCC characterized by fast growth might have a worse prognosis after surgery and adjuvant conventional ra- diotherapy and might benefit from more aggressive radiother- apeutic modalities. Key words: cell kinetics, head and neck cancer, surgery, radiotherapy. Introduction Surgery and radiotherapy are generally recognized as the up-front treatments for squamous cell carcinoma of the head and neck (HN-SCC)3o. Radiotherapy is indicat- ed when tumors are small or unresectable or when or- gan function preservation is desirable. Surgery is prefer- able when tumors are locally advanced but still amenable to radical excision. Adjuvant radiotherapy is usually recommended when histopathological analysis of the excised tumor specimen shows one or more fac- tors predicting a high risk of local relapse, i.e., evidence of tumor cells close to the excision margins, perivascu- lar and perineural invasion, gross primary tumor, lymph nodes with extracapsular invasion, or multiple-level lymph node involvernent'". Conventional radiotherapy consisting of 25-30 frac- tions of 2 Gy/day over 5-6 weeks, one fraction a day, is generally recommended in patients at high risk of re- lapse. Nevertheless, also after adjuvant radiotherapy the likelihood of local relapse remains about 25-30% within 18-24 months from surgery". This clinical observation indicates that residual tumor clones in the surgical bed may be radioresistant or may proliferate in spite of radi- ation treatments. In particular, clinical and experimental studies have pointed to the possibility that after surgery accelerated repopulation of residual tumor clonogens may occur as a response to surgical tumor debulking. This repopulation effect may be more marked for tu- mors showing a rapid proliferation rate at the time of surgery, i.e. unperturbed growth. Thus, the evaluation of tumor kinetics parameters during surgery may be useful to predict the proliferation rate of residual tumor cells during postoperative adjuvant radiotherapy and may help to correlate biological parameters with the risk of local failure 3.7 • 2o. The main purpose of this study was to evaluate whether pretreatment cell kinetics studied in a group of 35 HN-SCC patients submitted to radical surgery could help predict locoregional control after adjuvant conven- tional radiotherapy. S-phase fraction labeling index (LI%), duration of S phase (Ts), potential doubling time (Tpot) and DNA ploidy were determined in individual pa- tients with the in vivo bromodeoxyuridine (BrdUrd)/flow cytometry approach 4,9,1O,1l,31. A further aim of the study was to select a subgroup of rapidly proliferating tumors that might benefit from adjuvant accelerated radiotherapy. Material and methods Patient population Thirty-five patients with squamous cell carcinoma of the oral cavity (n = 14), oropharynx (n = 5) and larynx Acknowledgments: This work was supported by a grant from the Italian National Research Council (CNR-ACRO No. 96.00256.PF39). To whom correspondence should be addressed: Renzo Corvo, MD, Department of Radiotherapy, Istituto Nazionale per la Ricerca sui Cancro (1ST),largo Rosanna Benzi 10, 16132 Genova, Italy. Fax +39-010-5600039; e-mail corvo@hp380.ist.unige.it Received July 18, 1999; accepted September 27, 1999.