Dose-Limiting

Abstract: The introduction of multimodal management to cancer treatment has resulted in differences in the patterns of toxicity and therefore in end results reporting. The radiation oncologist is concerned with late effects whereas the chemotherapist is more limited by acute toxicities. The final dose chosen by a radiation oncologist is a combination of the fractionation schedules and the total dose in a total time period. This is modified only in some anatomic sites by an acute reaction but is more likely to be chosen because of a concept of an accumulated dose reaching a threshold. This threshold dose concept is based upon organ tolerance and has been defined as the radiation tolerance dose (TD) that causes 5% or 50% of severe complications in 5 years, that is, TD 5/5 and TD 50/5.2 In contrast, the dose limiting factors for chemotherapy administration are more often the maximum tolerated dose per cycle and the resulting acute reaction.4 The cyclic dose may produce acute effects such that there is dose modification based upon the toxicity level. The maximum tolerated dose, akin to threshold dose, is less often known for chemotherapeutic agents than for radiation late effects. As a result of the interaction of these two major treatment modalities-radiation and chemotherapy, and their differences in toxicity, two different scoring or grading systems have emerged. The radiation scores have been oriented to the specific pathologic lesions of late effects which are usually permanent whereas the chemotherapy grades usually reflect functional or physiologic effects which tend to be reversible. There has been a tendency, when both modalities are combined, to refer to the late normal tissue reactions as “recall phenomena.” However, the recent literature recognizes that radiation and chemotherapy may be additive in producing late effect injury’ and that chemotherapy alone can lead to an unsuspected late complication without an obvious acute phase much as is true for irradiation. Toxicity reporting of multi-agent chemotherapy combinations and/or their interaction with radiation effects has lead national cooperative groups to form committees to assess late effects and develop Scoring or Grading Systems for the toxicities resulting from combined cancer treatment, As a starting point for developing a uniform scoring system, a review and compilation of these systems has been undertaken. An analysis of endpoints, the diagnostic tests to assess them, their reversibility and treatability as documented by ten major investigative cooperative groups forms the basis of this position paper. A recommendation for a uniform system is the endproduct based upon extraction of the “consensus criteria”-that is, the similar features recurring in each of the cooperative group’s toxicity charts.