Cancer is a disease of the elderly (60% occur beyond the age of 65). It is also the second cause of death in older Americans, after cardiovascular diseases. Chemotherapy is a mainstay of its treatment, and being able to deliver it safely while minimizing dose reductions is essential to its effectiveness. Typically, in cancer trials, dose reductions are made for grade 3-4 non-hematologic toxicity or grade 4 hematologic toxicities (hereafter """"""""severe toxicity""""""""). Our research, notably the CRASH project (grant ACS RSG-03-151-01-CCE), has demonstrated that 2/3 of older chemotherapy-treated patients have a severe toxicity. Yet, this toxicity appears to have only a low impact on their functional status (Chen et al. 2003) and the dose-intensity of their treatment in clinical practice (Extermann et al. 2002). It also appears to generate a variable response by oncologists. Our recent data show that only 57% of patients undergo a change in their regimen after a severe toxicity, whereas 43% do not (O'Leary 2008). Counter-intuitively, the 1st group had a 37% recurrence of severe toxicity, whereas the 2nd only had a 17% recurrence rate (Odds ratio 2.85, p = 0.0075). This suggests that oncologists, somehow, are able to identify differential risk factors for toxicity recurrence. Baseline parameters and toxicity types were not correlated with this outcome. Our data imply that standard dose reduction schemes are not well adapted to older patients, with a potential for undertreating them. Given the 2 to 3-fold difference in risk of recurrence of severe toxicity between the two subgroups, there is a clear clinical need to understand the factors underlying this, and an opportunity for meaningful improvement. This R03 is aimed at designing an improved dose modification scheme for older patients that will be compared to standard dose-modification schemes in a randomized trial. We hypothesize that taking into account the duration of toxicity and its impact on the patient's function would lead to better treatment adaptations. I.e., for a same CTC grade, severe short, rapidly reversed toxicities with low impact on the patient's function would not lead to changes in treatment and have low risk of recurrence, whereas protracted toxicities would be more likely to recur, and might also highlight a decreased patient functional reserve. The present project will be derived from the methodology of the CRASH trial, with the focus shifted from understanding pretreatment risk factors for toxicity to the assessing the first period of severe toxicity, and its risk of recurrence. We will accrue a cohort of 200 patients aged 65 and older undergoing chemotherapy. Predictors associated with dose maintenance and recurrence of severe toxicity will be identified, and a dose-modification scheme optimizing dose maintenance without recurrence of severe toxicity will be designed, using cost-effectiveness type modeling. The research and clinical significance of this project is potentially large. Present protocols have dose reduction guidelines based strictly on CTC severity criteria. A better model might contribute to an improved treatment and outcomes for a third of older cancer patients on chemotherapy. It might also lead to more elderly-inclusive clinical trial designs.
The current rules to modify chemotherapy after a severe side effect do not appear well adapted to older patients. They might lead to too little treatment in some and a recurrence of severe side effects in others.
The Aim of this study is to design a better scheme for dose modification.
|Lee, Jae Jin; Kim, Jongphil; Sehovic, Marina et al. (2017) Using heat maps to assess the multidimensional association of comorbidities with survival in older cancer patients treated with chemotherapy. J Geriatr Oncol 8:336-342|
|Extermann, Martine; Reich, Richard R; Sehovic, Marina (2015) Chemotoxicity recurrence in older patients: Risk factors and effectiveness of preventive strategies-a prospective study. Cancer 121:2984-92|