Towards prediction and modulation of treatment response

The purpose of this paper is to evaluate new predictive assays and their po tential to modulate treatment response. Their impact is presented in the co ntext of three EORTC clinical trials in head and neck, lung and breast canc er, showing an improvement in survival by accelerated fractionation, concom itant use of cisplatin and radiotherapy and adjuvant hormonal treatment, re spectively. Assays have been developed to predict the response to treatment by measurin g tumor characteristics, such as the growth potential by the labeling index after i.v. injection of IdUrd, the extent of radiation-induced stable and unstable chromosome aberrations and the induction of apoptosis. These assay s could guide us in the adaptation of the individual radiation doses and fr actionation schedules. The measurement of the effect of cisplatin on DNA has become feasible with the development of antibodies against DNA adducts. In a recently completed phase II dose escalation trial with concomitant radiotherapy and daily cisp latin in lung cancer, we found that patients with high DNA adduct levels me asured in the buccal mucosa, had a much better survival rate than patients with a low or undetectable amount of cisplatin DNA adducts. A better understanding of the signal transduction pathways involved in radi ation-induced apoptosis may help to design studies aimed at modulating the apoptotic response. We and others have recently shown that alkylphospholipi ds, which inhibit mitogenic signaling, induce apoptosis in a variety of tum or cell lines. In combination with ionizing radiation, these compounds caus e an enhancement of apoptotic cell kill. This type of signaling-based inter vention study may form the basis for new therapeutic strategies. Pretreatme nt levels of apoptosis may be helpful in predicting treatment outcome, alth ough the data so far show inconsistent results. The importance of evaluatin g other tumor-biological parameters, including cell kinetics should be stre ssed. Based on assays predicting reliably the response to hormonal therapy, a mor e appropriate choice can be made for therapeutic intervention with hormonal therapy and for selecting the appropriate adjuvant therapy in breast cance r patients. The development of a functional estrogen receptor assay (ER-FAS AY), based on a yeast growth-assay, provides a way of estimating abnormal f unction of the receptor in tumors with a positive estrogen receptor score a s measured by a classical immuno-histochemistry assay. This yeast assay can also detect different DNA mutations of the estrogen receptor existing in a n individual tumor specimen. (C) 1999 Elsevier Science Ireland Ltd. All rig hts reserved.