“New” metastases are associated with a poorer prognosis than growth of pre-existing metastases in patients with metastatic breast cancer treated with chemotherapy

Abstract

IntroductionProgression-free survival (PFS) and overall survival (OS) endpoints often only weakly correlate. This analysis investigates how different progression events impact on OS, using data from two phase 3 studies with eribulin in women with advanced/metastatic breast cancer (MBC).MethodsIn Study 301, 1102 women with ≤2 prior chemotherapies for advanced/MBC were randomized to eribulin mesylate (1.4 mg/m2 on days 1 and 8 every 21 days) or capecitabine (1.25 g/m2 twice daily on days 1–14 every 21 days). Study 305/EMBRACE enrolled 762 patients following two to five prior chemotherapies for advanced/MBC, randomized to eribulin (as above) or treatment of physician’s choice. We analyzed OS and PFS post hoc for patients whose disease progressed due to development of “new” metastases, growth of pre-existing lesions, and patients with no reported disease progression.ResultsIn both clinical studies, development of new metastases was associated with an increased risk of death (p < 0.0001). The time to development of new metastasis or death was significantly longer with eribulin than the comparator in Study 305 (p = 0.0017), but not in Study 301 (p = 0.46). Significantly longer OS was observed in the eribulin compared with the comparator arm for the new metastases subgroup in Study 301 (p = 0.008), but not in Study 305 (p = 0.16), compared with other progression subgroups.ConclusionsPatients with MBC progressing with new metastases have a worse prognosis than those whose disease progresses due to growth of existing lesions or patients with no reported disease progression. These findings have potentially important implications for the interpretation of clinical study data and clinical practice.Trial registrationClinicalTrials.gov registration IDs: Study 301: NCT00337103; Study 305: NCT00388726.

Phase Ib Pilot Study to Evaluate Reparixin in Combination with Weekly Paclitaxel in Patients with HER-2–Negative Metastatic Breast Cancer

“…One potential surrogate endpoint is the development of metastases at new sites [30, 31]. It is hypothesized that a successful anti-CSC treatment will impact on the time to developing new metastases and on the proportion of patients progressing with new metastases rather than on the progression of pre-existing metastases which is likely due to non-BCSC, bulk tumor cells.…”

Impact of progression type on overall survival in patients with advanced gastric cancer based on randomized phase III study of S-1 plus oxaliplatin versus S-1 plus cisplatin

“…It has also been used in earlier studies in other cancers [4,5]. We believe that this is the best approach in this setting.…”

“…One earlier study of breast cancer suggested that a new endpoint, defined as the time from randomization to progression with new metastasis or death, might improve the predictivity on OS [4]. It has been noted that it can be difficult to identify progression and measure lesions accurately by assessing pre-existing lesions, especially when the baseline lesions are small [13].…”

“…Therefore, the European Medicines Agency guideline recommends each individual event be analyzed and reported separately [3]. One randomized phase III study of breast cancer demonstrated that the prognosis in patients with new metastatic lesions was less favorable than in those with increased size of preexisting lesions [4]. This suggests that progression type might likewise affect the prognosis in gastric cancer as well.…”

“…In investigating the association between various events occurring in a trial and OS, the standard approach adopted in many studies has been to employ a Cox regression model using time-dependent covariates [4][5][6][7][8][9]. However, the association between progression type and survival remains to be investigated by this method in gastric cancer.…”