Original Article
Chemotoxicity Recurrence in Older Patients: Risk Factors and Effectiveness of Preventive Strategies—A Prospective Study Martine Extermann, MD1,2; Richard R. Reich, MD1,3; and Marina Sehovic, MD1
BACKGROUND: The National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE) and adjustment rules after severe toxicity are derived by consensus, but to the authors’ knowledge little is known regarding the determinants of toxicity recurrence, especially in the elderly. METHODS: The authors prospectively accrued 200 patients (aged 65 years) before chemotherapy. For those with CTCAE grade 3 to 4 nonhematologic or CTCAE grade 4 hematologic toxicities (severe toxicity), the duration and functional impact, treatment modifications, and severe toxicity recurrence were recorded. The regimen’s toxicity was adjusted with the MAX2 index, the average of the most frequent grade 4 hematologic toxicities and the most frequent grade 3 to 4 nonhematologic toxicities reported in publications of a regimen. RESULTS: The median patient age was 73 years (range, 65-90 years). Among 163 patients who were evaluable for toxicity after 1 treatment cycle (receiving on average 4.73 cycles), 82 had severe toxicity, 10 were discontinued for toxicity, 6 were discontinued for other reasons, and 5 patients had died. Sixty-one patients received further chemotherapy: 41 without dose modification (16 with secondary prevention measures) and 20 with dose modifications. Without modification, 19 patients (46%) experienced toxicity recurrence (0 deaths). With modification, 7 patients (35%) experienced a toxicity recurrence (1 death). On univariate analysis, treatment intent, hospitalization, duration-adjusted activities of daily living (ADL), quality of life impact, and fatigue were associated with dose modification. ADL remained associated on multivariate analysis (P 5.02). On univariate analysis for toxicity recurrence, Eastern Cooperative Oncology Group performance status and MAX2 score demonstrated an association, with only the latter found to remain statistically significant on multivariate analysis (P 5.04). CONCLUSIONS: If a severe toxicity does not have a long duration of impact on ADL, oncologists are less inclined to modify treatment. With proper supportive measures, this leads to recurrence risks similar to those shown in patients with modified treatment, with low risks of toxic C 2015 American Cancer Society. deaths overall. Cancer 2015;121:2984-92. V KEYWORDS: chemotherapy, elderly, chemotherapy toxicity, management of chemotherapy toxicity, MAX2 index, geriatric oncology, functional status, quality of life, Common Terminology Criteria for Adverse Events (CTCAE).
INTRODUCTION Assessing the severity of side effects from chemotherapy in a reproducible manner is a familiar issue for clinical trialists. Over the years, the National Cancer Institute has developed a consensus definition: the Common Terminology Criteria for Adverse Events (CTCAE), which is currently in its fourth version.1 Clinical trials often recommend treatment modification in cases of grade 4 hematologic or grade 3 to 4 nonhematologic toxicity. Although grade 3 hematologic toxicity is often lumped in with the group, dose modifications are rarely recommended for patients with grade 3 neutropenia or leukopenia, which are the most frequent of these toxicities by far. Grade 4 hematologic toxicity and/or grade 3 to 4 nonhematologic toxicity (hereafter called “severe toxicity”) is experienced by 50% of older patients with cancer in a clinical setting.2,3 However, we observed that the functional impact of those toxicities is variable and that chemotherapy is often continued at good doses.2 When we further explored the appropriateness of this management approach, we were surprised to note that, in clinical practice, approximately 40% of older patients did not have dose modifications and that this appeared to be safe, with actually fewer recurrences of toxicities noted among the patients without dose modifications.4 Because no direct correlation with patients’ baseline characteristics was noted, this suggested some factor recognized by the clinician at the time of toxicity. We hypothesized that, if a severe toxicity was of short duration and did not have a functional impact, it would be safe to continue the chemotherapy at full dose. Furthermore, identifying older patients at low risk of further toxicity has a clear potential for improving treatment delivery and patient outcomes. In the current study,
Corresponding author: Martine Extermann, MD, Senior Adult Oncology Program, H. Lee Moffitt Cancer Center, 12902 Magnolia Dr, Tampa, FL 33612; Fax: (813) 745-1908; [email protected] 1 Senior Adult Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida; 2Dept of Oncology Sciences, University of South Florida, Tampa, Florida; 3Department of Psychology, College of Arts and Sciences, University of South Florida Sarasota-Manatee, Sarasota, Florida.
We thank Rasa G. Hamilton, ELS, for her editorial assistance. DOI: 10.1002/cncr.29423, Received: September 11, 2014; Revised: March 26, 2015; Accepted: March 26, 2015, Published online May 29, 2015 in Wiley Online Library (wileyonlinelibrary.com)
2984
Cancer
September 1, 2015
Toxicity Recurrence and Prevention/Extermann et al
we addressed 2 questions: 1) do short toxicities with low functional impact correlate with maintenance of treatment dose by the oncologist and 2) does that targeted dose maintenance lead to an equal or lower rate of toxicity recurrence versus that shown in patients who had dose modification after toxicity? MATERIALS AND METHODS The current study was a prospective observational cohort study of patients treated with chemotherapy at the H. Lee Moffitt Cancer Center. Patients had to be aged 65 years and have a histologically or cytologically documented malignant tumor. A chemotherapy regimen that included at least 1 classic chemotherapy agent had to be planned. The chemotherapy regimen and management were left to the discretion of the treating oncologist, provided it was a published regimen and was not an aplasiant treatment (eg, an acute leukemia or a transplant regimen). The toxicity of the regimen was rated with the MAX2 index.2,5 Briefly, the MAX2 index is the average of the most frequent grade 4 hematologic toxicity and the most frequent grade 3 to 4 nonhematologic toxicity reported in publications of a regimen and correlates well with the average overall risk of severe toxicity for that regimen. Exclusion criteria were diagnosis of dementia, chemotherapy administered within
Chemotoxicity Recurrence in Older Patients: Risk Factors and Effectiveness of Preventive Strategies—A Prospective Study Martine Extermann, MD1,2; Richard R. Reich, MD1,3; and Marina Sehovic, MD1
BACKGROUND: The National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE) and adjustment rules after severe toxicity are derived by consensus, but to the authors’ knowledge little is known regarding the determinants of toxicity recurrence, especially in the elderly. METHODS: The authors prospectively accrued 200 patients (aged 65 years) before chemotherapy. For those with CTCAE grade 3 to 4 nonhematologic or CTCAE grade 4 hematologic toxicities (severe toxicity), the duration and functional impact, treatment modifications, and severe toxicity recurrence were recorded. The regimen’s toxicity was adjusted with the MAX2 index, the average of the most frequent grade 4 hematologic toxicities and the most frequent grade 3 to 4 nonhematologic toxicities reported in publications of a regimen. RESULTS: The median patient age was 73 years (range, 65-90 years). Among 163 patients who were evaluable for toxicity after 1 treatment cycle (receiving on average 4.73 cycles), 82 had severe toxicity, 10 were discontinued for toxicity, 6 were discontinued for other reasons, and 5 patients had died. Sixty-one patients received further chemotherapy: 41 without dose modification (16 with secondary prevention measures) and 20 with dose modifications. Without modification, 19 patients (46%) experienced toxicity recurrence (0 deaths). With modification, 7 patients (35%) experienced a toxicity recurrence (1 death). On univariate analysis, treatment intent, hospitalization, duration-adjusted activities of daily living (ADL), quality of life impact, and fatigue were associated with dose modification. ADL remained associated on multivariate analysis (P 5.02). On univariate analysis for toxicity recurrence, Eastern Cooperative Oncology Group performance status and MAX2 score demonstrated an association, with only the latter found to remain statistically significant on multivariate analysis (P 5.04). CONCLUSIONS: If a severe toxicity does not have a long duration of impact on ADL, oncologists are less inclined to modify treatment. With proper supportive measures, this leads to recurrence risks similar to those shown in patients with modified treatment, with low risks of toxic C 2015 American Cancer Society. deaths overall. Cancer 2015;121:2984-92. V KEYWORDS: chemotherapy, elderly, chemotherapy toxicity, management of chemotherapy toxicity, MAX2 index, geriatric oncology, functional status, quality of life, Common Terminology Criteria for Adverse Events (CTCAE).
INTRODUCTION Assessing the severity of side effects from chemotherapy in a reproducible manner is a familiar issue for clinical trialists. Over the years, the National Cancer Institute has developed a consensus definition: the Common Terminology Criteria for Adverse Events (CTCAE), which is currently in its fourth version.1 Clinical trials often recommend treatment modification in cases of grade 4 hematologic or grade 3 to 4 nonhematologic toxicity. Although grade 3 hematologic toxicity is often lumped in with the group, dose modifications are rarely recommended for patients with grade 3 neutropenia or leukopenia, which are the most frequent of these toxicities by far. Grade 4 hematologic toxicity and/or grade 3 to 4 nonhematologic toxicity (hereafter called “severe toxicity”) is experienced by 50% of older patients with cancer in a clinical setting.2,3 However, we observed that the functional impact of those toxicities is variable and that chemotherapy is often continued at good doses.2 When we further explored the appropriateness of this management approach, we were surprised to note that, in clinical practice, approximately 40% of older patients did not have dose modifications and that this appeared to be safe, with actually fewer recurrences of toxicities noted among the patients without dose modifications.4 Because no direct correlation with patients’ baseline characteristics was noted, this suggested some factor recognized by the clinician at the time of toxicity. We hypothesized that, if a severe toxicity was of short duration and did not have a functional impact, it would be safe to continue the chemotherapy at full dose. Furthermore, identifying older patients at low risk of further toxicity has a clear potential for improving treatment delivery and patient outcomes. In the current study,
Corresponding author: Martine Extermann, MD, Senior Adult Oncology Program, H. Lee Moffitt Cancer Center, 12902 Magnolia Dr, Tampa, FL 33612; Fax: (813) 745-1908; [email protected] 1 Senior Adult Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida; 2Dept of Oncology Sciences, University of South Florida, Tampa, Florida; 3Department of Psychology, College of Arts and Sciences, University of South Florida Sarasota-Manatee, Sarasota, Florida.
We thank Rasa G. Hamilton, ELS, for her editorial assistance. DOI: 10.1002/cncr.29423, Received: September 11, 2014; Revised: March 26, 2015; Accepted: March 26, 2015, Published online May 29, 2015 in Wiley Online Library (wileyonlinelibrary.com)
2984
Cancer
September 1, 2015
Toxicity Recurrence and Prevention/Extermann et al
we addressed 2 questions: 1) do short toxicities with low functional impact correlate with maintenance of treatment dose by the oncologist and 2) does that targeted dose maintenance lead to an equal or lower rate of toxicity recurrence versus that shown in patients who had dose modification after toxicity? MATERIALS AND METHODS The current study was a prospective observational cohort study of patients treated with chemotherapy at the H. Lee Moffitt Cancer Center. Patients had to be aged 65 years and have a histologically or cytologically documented malignant tumor. A chemotherapy regimen that included at least 1 classic chemotherapy agent had to be planned. The chemotherapy regimen and management were left to the discretion of the treating oncologist, provided it was a published regimen and was not an aplasiant treatment (eg, an acute leukemia or a transplant regimen). The toxicity of the regimen was rated with the MAX2 index.2,5 Briefly, the MAX2 index is the average of the most frequent grade 4 hematologic toxicity and the most frequent grade 3 to 4 nonhematologic toxicity reported in publications of a regimen and correlates well with the average overall risk of severe toxicity for that regimen. Exclusion criteria were diagnosis of dementia, chemotherapy administered within
