Clinical parameters to guide decision-making in elderly metastatic colorectal cancer patients treated with intensive cytotoxic and anti-angiogenic therapy

Abstract

IntroductionBevacizumab addiction to triplet chemotherapy, according to FIr-B/FOx schedule, as first-line treatment in young-elderly metastatic colorectal CANCER (MCRC) patients may be more effective. Tailored treatments show worse clinical outcome in unfit patients.MethodsElderly patients were clinically evaluated according to age and comorbidity (Cumulative Illness Rating Scale) to select FIr-B/FOx regimen in fit or tailored treatments in unfit elderly. Limiting toxicity syndromes (LTS) were evaluated.ResultsAt 17 months follow-up, in 28 young-elderly patients treated with first line FIr-B/FOx: objective response rate (ORR) 79%, progression-free survival (PFS) 11 months, overall survival (OS) 21 months. Clinical outcome was not significantly different according to KRAS genotype. G3-4 toxicities were diarrhea 21%, mucositis 11%, neutropenia 11%. LTS were 46%, significantly more multiple than single site. At 8 months follow-up, in 37 unfit patients: ORR 37%, PFS 7 months, OS 13 months. PFS was significantly different in KRAS wild-type compared to mutant patients, while not OS. PFS and OS were significantly worse in KRAS c.35 G > A compared to wild-type and/or other mutant.ConclusionsCareful decision-making process including evaluation of patient's fitness, and individual safety should be included to select FIr-B/FOx intensive first line regimen in young-elderly MCRC patients. KRAS, and specifically c.35 G > A mutant genotype, may significantly affect clinical outcome in patients unfit for FIr-B/FOx.

Toxicity Syndromes, Patient-Related Clinical Indicator of Toxicity Burden Induced by Intensive Triplet Chemotherapy-Based Regimens in Gastrointestinal Cancers With Metastatic Disease

“…Clinical status of the individual patient, also depending from metastatic tumor extension, is the most important variable justifying differential toxicity in individual patients. Thus, patients treated with triplet chemotherapy-based regimens should be enrolled by careful decision-making including age, PS, and comorbidity status (19,20,26,27). To this aim, FIr-B/FOx (2) as first line treatment of mCRC patients gained equivalent efficacy than that reported with triplet schedules, such as FOLFOXIRI/BEV (2,3,28), and demonstrated a good tolerability profile (1,29), with lower G3-4 neutropenia, also in yE mCRC patients (20,27).…”

“…Thus, patients treated with triplet chemotherapy-based regimens should be enrolled by careful decision-making including age, PS, and comorbidity status (19,20,26,27). To this aim, FIr-B/FOx (2) as first line treatment of mCRC patients gained equivalent efficacy than that reported with triplet schedules, such as FOLFOXIRI/BEV (2,3,28), and demonstrated a good tolerability profile (1,29), with lower G3-4 neutropenia, also in yE mCRC patients (20,27). C addiction according to FIr-C/FOx-C schedule in KRAS/NRAS wild-type mCRC (4) met the projected high activity, as different other schedules of C addition to triplet chemotherapy, chrono-IFLO, ERBIRINOX, FOLFOXIRI (5)(6)(7)(8), or panitumumab addiction to modified FOLFOXIRI (9, 10), even if individual toxicity profile limited the wide use of intensive schedules associating triplet chemotherapy and anti-EGFR targeted agents in clinical practice, thus requiring pharmacogenomic analysis to more properly select fit mCRC patients (4).…”

“…In yE patients, LTS evaluation showed the differential tolerability of intensive triplet chemotherapy based regimens: in mCRC, FIr-B/FOx LTS 46%, but significantly prevalent LTSms (20,27); FIr-C/FOx-C LTS 83%, pointing elderly status ≥65 years as an exclusion criteria for intensive regimens adding triplet chemotherapy to anti-EGFR. In mPDAC patients, FIr/FOx LTS 38.4%; in mGC patients treated with FD/FOx, LTS 25%.…”

Intensive first line FIr-C/FOx-C association of triplet chemotherapy plus cetuximab in RAS wild-type metastatic colorectal cancer patients: Preliminary phase II data and prediction of individual limiting toxicity syndromes by pharmacogenomic biomarkers.

“…To this aim, as previously proposed, we added the evaluation of individual LTS, in order to more properly evaluate the clinical relevance of toxicity in individual patients. 3,26,27 Overall, the FIr-C/ FOx-C schedule determined 65.5% of individual LTS, significantly more represented by LTS-ms (59%) than LTS-ss (p = 0.006), mostly characterized by LT associated with other at least grade 2 non-limiting toxicities (34%) or ⩾2 LTs (24%), prevalently diarrhea and asthenia associated with other toxicities, or skin rash and stomatitis/ mucositis associated with asthenia and diarrhea. LTS were previously observed in 44% of MCRC patients treated with FIr-B/FOx, and equally involving single or multiple sites.…”

“…LTS, consisting of at least one LT associated or not with other limiting or grade 2 toxicities, were evaluated, 3,26,27 and classified as: LTS single site (LTS-ss), if characterized only by the LT; LTS multiple sites (LTS-ms), if characterized by ⩾2 LTs or an LT associated with other, at least grade 2, non-limiting toxicities. A Chi-square test was used to compare the rates of LTS-ms and LTS-ss.…”