Peritoneal metastasis as a predictive factor for nab-paclitaxel in patients with pretreated advanced gastric cancer: an exploratory analysis of the phase III ABSOLUTE trial

Peritoneal metastasis as a predictive factor for nab-paclitaxel in patients with pretreated... Background In the ABSOLUTE trial, weekly nanoparticle albumin-bound paclitaxel (w-nab-PTX) showed non-inferiority to weekly solvent-based paclitaxel (w-sb-PTX) for overall survival (OS). Thus, w-nab-PTX might be an option for second- line chemotherapy in advanced gastric cancer (AGC). However, predictive factors for efficacies of these agents have not been evaluated. Methods Patients previously enrolled in the ABSOLUTE trial were divided into apparent peritoneal metastasis group (PM group) and no apparent peritoneal metastasis group (no PM group) based on baseline imaging evaluated by RECIST ver. 1.1 criteria and amount of ascites. OS, progression-free survival, and overall response rate were compared between two arms in each group. Results This study included 240 and 243 patients in the w-nab-PTX and w-sb-PTX arms, respectively. In the PM group, the w-nab-PTX arm (n = 88) had longer OS than the w-sb-PTX arm (n = 103), and median survival time (MST) of 9.9 and 8.7 months [hazard ratio (HR) 0.63; 95% CI 0.45–0.88; P = 0.0060], respectively. In the no PM group, the w-nab-PTX arm (n = 140) had shorter OS than the w-sb-PTX arm (n = 152), and MST of 11.6 and 15.7 months (HR 1.40; 95% CI 1.06–1.86; P = 0.0180), respectively. After adjusting for prognostic factors, the HR for OS in the w-nab-PTX arm versus the w-sb-PTX arm was 0.59 (95% CI 0.42–0.83; P = 0.0023; PM group) and 1.34 (95% CI 1.01–1.78; P = 0.0414; no PM group), with significant interaction between treatment efficacy and presence of peritoneal metastasis (P = 0.0003). Conclusions The presence of apparent peritoneal metastasis might be a predictive factor for selecting w-nab-PTX for pre- treated AGC patients. Trial registration number JapicCTI-132059. Keywords Peritoneal metastasis · Nab-paclitaxel · Solvent-based paclitaxel · Second-line chemotherapy · Predictive factor Introduction Solvent-based paclitaxel (sb-PTX) is one of the standard second-line chemotherapies for advanced gastric cancer (AGC). Recently, the ABSOLUTE trial compared the effi- Electronic supplementary material The online version of this cacy and safety of nanoparticle albumin-bound paclitaxel article (https ://doi.org/10.1007/s1012 0-018-0838-6) contains 2 (nab-PTX) (260  mg/m )  of every 3  weeks schedule and supplementary material, which is available to authorized users. weekly nab-PTX (100 mg/m ) (w-nab-PTX) with that of weekly sb-PTX (80 mg/m ) (w-sb-PTX) in patients with * Atsuo Takashima atakashi@ncc.go.jp AGC refractory to a fluoropyrimidine-containing chemo- therapy regimen [1]. The non-inferiority of w-nab-PTX to Extended author information available on the last page of the article Vol.:(0123456789) 1 3 A. Takashima et al. w-sb-PTX in overall survival (OS) was confirmed, while that 30 min on days 1, 8, and 15 every 4 weeks (1 cycle), while of nab-PTX (every 3 weeks) to w-sb-PTX was not. Based on those in the w-sb-PTX arm received 80 mg/m intravenous the ABSOLUTE trial results, w-nab-PTX might be an option sb-PTX over 60 min after pre-medication with steroids and for second-line chemotherapy for AGC. However, a predic-histamine H receptor antagonists on days 1, 8, and 15 every tive factor for selecting either w-sb-PTX or w-nab-PTX is 4 weeks (1 cycle). not yet available. The review board at each participating institution The peritoneum is among the most frequent metastatic approved this trial, which was conducted according to the sites of AGC. Moreover, the frequency of peritoneal metas- Declaration of Helsinki, International Conference on Har- tasis increases with the clinical course; it is more common monisation, and Good Clinical Practice. All patients pro- in pretreated patients with AGC than in chemotherapy-naïve vided written informed consent. patients. Several phase II trials showed the promising effi - cacy of w-sb-PTX for patients with AGC with peritoneal Classification of peritoneal metastasis metastasis [2, 3]. A subgroup analysis of the ABSOLUTE trial suggested that w-nab-PTX showed more favorable effi- We used two factors to classify peritoneal metastasis based cacy than w-sb-PTX in patients with peritoneal metastasis. on baseline imaging. First was the presence of detectable Furthermore, the effect of w-nab-PTX was correlated with peritoneal lesions by investigator-judged imaging, either the amount of ascites [1]. W-nab-PTX is speculated to have measurable or non-measurable according to RECIST ver. advantages over w-sb-PTX depending on the severity of 1.1, such as peritoneal nodules, thickening of the mesente- peritoneal metastasis. rium, and bowel deformity or obstruction. Second was the However, criteria for evaluating the severity of peritoneal amount of ascites evaluated by investigator-judged imaging. metastasis have not been established; neither the presence Small and large amounts of ascites were defined as “ascites of peritoneal lesions detected by imaging nor the amount limited to the pelvic cavity” and “ascites from the pelvis of ascites appropriately reflect the severity of peritoneal extending continuously to the upper abdomen”, respectively. metastasis. Some patients were diagnosed with peritoneal A moderate amount of ascites was termed “ascites other metastasis via staging laparoscopy before the initiation of than small or large ascites”. Patients were categorized as first-line chemotherapy and without peritoneal lesions or having “massive ascites” (presence of large or moderate ascites detectable by imaging before the start of second- ascites) or “no massive ascites” (presence of small ascites line chemotherapy. While some patients have ascites without or no ascites). visible peritoneal lesions such as peritoneal nodules, thick- Using these two categories, the subjects were classified ening of the mesenterium, and bowel deformity or obstruc- into four groups: group A comprised patients with no detect- tion, visible peritoneal metastasis is sometimes not associ- able peritoneal lesions and no massive ascites; group B is ated with ascites. Therefore, neither the presence of visible comprised of patients with detectable peritoneal lesions and peritoneal lesions nor ascites alone is adequate for selecting no massive ascites; group C is comprised of patients with no which regimen, w-nab-PTX or w-sb-PTX, is optimal for the detectable peritoneal lesions and massive ascites; and group patient. Moreover, the subgroup analysis of the ABSOLUTE D is comprised patients of with detectable peritoneal lesions trial was not adjusted by prognostic factors between the two and massive ascites. Furthermore, patients in groups B, C, arms. and D who had apparent peritoneal metastasis were uni- In this study, we compared the efficacy of w-nab-PTX and fied to the apparent peritoneal metastasis group (PM group), w-sb-PTX according to the severity of peritoneal metastasis while patients in group A who did not have apparent perito- based on visible peritoneal lesions and amount of ascites. neal metastasis were assigned to the no apparent peritoneal metastasis group (no PM group). Methods Statistical analysis Patients and methods The efficacy endpoints of this study were OS, progression- free survival (PFS), and overall response rate (ORR). Sur- A total of 742 patients were enrolled in the ABSOLUTE trial vival curves were estimated using the Kaplan–Meier method. between March 2013 and May 2015. We selected patients The hazard ratio (HR) and P value for OS and PFS of the allocated to the w-nab-PTX and w-sb-PTX arms, because w-nab-PTX group compared with the w-sb-PTX group were w-nab-PTX showed non-inferiority to w-sb-PTX in terms calculated using the Cox proportional hazard model. ORR of OS in the ABSOLUTE trial. The presence of peritoneal was analyzed in patients with at least one measurable lesion metastasis was a stratification factor. Patients in the w-nab- at baseline. We used Fisher’s exact test to compare the ORR PTX arm received 100 mg/m intravenous nab-PTX over between the two treatment groups and the logistic regression 1 3 Peritoneal metastasis as a predictive factor for nab-paclitaxel in patients with pretreated… model to assess the interaction for ORR among the groups. two treatment arms (median PFS: 4.9 months for w-nab-PTX To adjust the confounding factors and assess interaction and 3.8 months for w-sb-PTX; HR 1.02; 95% CI 0.80–1.30; between treatment groups (w-nab-PTX and w-sb-PTX) and P = 0.888) (Fig.  2a). In a multivariate analysis adjusting subgroups of peritoneal metastasis (peritoneal metastasis for prognostic factors, the HR for PFS of the w-nab-PTX and non-peritoneal metastasis), we used the other prognostic arm compared with the w-sb-PTX arm was 0.54 (95% CI factors as covariates such as age, performance status, histo- 0.39–0.75; P = 0.0002) in the PM group and 0.93 (95% CI logical type, previous gastrectomy, type of treatment failure 0.72–1.20; P = 0.5734) in the no PM group. The interaction with previous chemotherapy, and duration of prior chemo- for PFS after adjusting for prognostic factors was significant therapy for multivariate analysis. The confidence coefficient between the PM and no PM groups (P = 0.0191). for the confidence interval of the median time and HR for In the PM group, 52/88 (59.1%) patients treated with OS and PFS, and ORR was set to 95% (P < 0.05). All analy- w-nab-PTX and 66/103 (64.1%) patients treated with w-sb- ses were performed using SAS version 9.2. PTX received post-study treatment (P = 0.551). In the no PM group, 101/152 patients (66.4%) treated with w-nab- PTX and 111/140 patients (79.3%) treated with w-sb-PTX Results received post-study treatment (P = 0.018) (Supplementary Table 2). A total of 483 patients were analyzed in this study. Among The median OS in the PM group was 9.9 months (95% them, 240 and 243 belonged to the w-nab-PTX and w-sb- CI 7.5–12.9) and 8.7  months (95% CI 7.7–9.2) for the PTX groups, respectively. All 483 patients were included in w-nab-PTX arm and the w-sb-PTX arm (HR 0.63; 95% CI the full analysis set for the primary analysis in the ABSO- 0.45–0.88; P = 0.0060), respectively (Fig. 2b). In a multi- LUTE trial. The patient characteristics are shown in Table 1; variate analysis adjusting for prognostic factors, the HR for the classification into groups A–D is shown in Supplemen- OS of the w-nab-PTX arm compared with the w-sb-PTX tary Fig. 1. arm was 0.59 (95% CI 0.42–0.83; P = 0.0023) in the PM The OS and PFS are summarized in Table 2 and the sur- group and 1.34 (95% CI 1.01–1.78; P = 0.0414) in the no vival curves in Fig. 1. The HRs for the OS of the w-nab- PM group. The interaction for OS was significantly differ - PTX arm compared with the w-sb-PTX arm in groups A, ent between the PM and no PM groups after adjusting for B, C, and D were 1.40 (95% CI 1.06–1.86; P = 0.018), 0.64 prognostic factors (P = 0.0003). For sensitivity analysis, we (95% CI 0.42–1.00; P = 0.046), 0.66 (95% CI 0.32–1.34; added the multivariate analysis of OS and PFS to include P = 0.245), and 0.47 (95% CI 0.22–1.00; P = 0.044), respec- the imbalanced factors of sex and the number of metastatic tively. The HRs for the PFS of the w-nab-PTX arm compared organs in addition to the original covariates. The results with the w-sb-PTX arm in groups A, B, C, and D were 1.02 of the additional analysis were similar to those of analy- (95% CI 0.80–1.30; P = 0.888), 0.62 (95% CI 0.42–0.93; ses undertaken without adjusting for sex and the number of P = 0.020), 0.77 (95% CI 0.38–1.54; P = 0.448), and 0.43 metastatic organs (data not shown). (95% CI 0.20–0.89; P = 0.019), respectively. The results for the ORR are summarized in Supplementary Table 1. The ORRs were not significantly different between the w-nab- PTX and w-sb-PTX arms except in group B [45.5% (15/33) Discussion vs. 15.9% (7/44), P = 0.0057]. In the PM group, the w-nab-PTX arm showed a higher To the best of our knowledge, this study is the first to assess ORR than the w-sb-PTX arm: 40.0% (16/40) for w-nab-PTX the efficacy of w-nab-PTX and w-sb-PTX based on perito- and 16.4% (9/55) for w-sb-PTX (P = 0.0172). The ORR in neal metastasis. We showed that w-nab-PTX yielded better the no PM group was similar in the two treatment arms: OS, PFS, and ORR than w-sb-PTX in patients with apparent 30.0% (33/110) for w-nab-PTX and 28.1% (32/114) for peritoneal metastasis. w-sb-PTX (P = 0.7702). In a multivariate analysis adjusting In this study, we divided the patients into four groups for prognostic factors, the odds ratio for ORR was 3.945 using two categories, the presence of detectable perito- (95% CI 1.402–11.102; P = 0.0093) in the PM group and neal lesions by imaging and the amount of ascites. Among 1.086 (95% CI 0.593–1.991; P = 0.7890) in the no PM the four groups, group D, containing patients with both group. The interaction for ORR after adjusting for prognos- detectable peritoneal lesions and massive ascites, showed tic factors was significant (P = 0.0174). the poorest prognosis, while group A, containing patients The median PFS in the PM group was 5.7 months (95% without detectable peritoneal lesions or massive ascites, CI 4.4–7.1) and 3.7 months (95% CI 3.4–3.9) for the w-nab- showed the best prognosis. Moreover, the prognosis of PTX arm (HR 0.62; 95% CI 0.46–0.85; P = 0.0024). In the patients in groups B and C were between groups A and D. no PM group (group A), the PFS was similar between the These results suggested that our classification of peritoneal 1 3 A. Takashima et al. Table 1 Baseline characteristics of patients in the four groups Group A (N = 292) Group B (N = 118) Group C (N = 38) Group D (N = 35) Total w-nab- w-sb-PTX w-nab- w-sb-PTX w-nab- w-sb-PTX w-nab- w-sb-PTX PTX (N = 140) PTX (N = 64) PTX (N = 19) PTX (N = 20) (N = 152) (N = 54) (N = 19) (N = 15) Age (years), n (%)  < 65 58 (38) 61 (44) 22 (41) 30 (47) 7 (37) 13 (68) 8 (53) 11 (55) 210  ≥ 65 94 (62) 79 (56) 32 (59) 34 (53) 12 (63) 6 (31) 7 (47) 9 (45) 273 Sex, n (%)  Female 38 (25) 31 (22) 11 (20) 19 (30) 8 (42) 12 (63) 5 (33) 5 (25) 129  Male 114 (75) 109 (78) 43 (80) 45 (70) 11 (58) 7 (37) 10 (67) 15 (75) 354 ECOG performance status, n (%)  0 115 (76) 112 (80) 29 (54) 32 (50) 12 (63) 11 (58) 12 (80) 13 (65) 336  1 35 (23) 25 (18) 25 (46) 32 (50) 7 (37) 7 (37) 3 (20) 7 (35) 141  2 2 (1) 3 (2) 0 0 0 1 (5) 0 0 6 Histological type, n (%)  Diffuse 73 (48) 66 (47) 37 (69) 36 (56) 15 (79) 16 (84) 12 (80) 14 (70) 269  Intestinal 79 (52) 74 (53) 17 (31) 28 (44) 4 (21) 3 (16) 3 (20) 5 (25) 213  Unknown 0 0 0 0 0 0 0 1 (5) 1 Previous gastrectomy, n (%)  No 73 (48) 64 (46) 21 (39) 28 (44) 5 (26) 8 (42) 10 (67) 11 (55) 220  Yes 79 (52) 76 (54) 33 (61) 36 (56) 14 (74) 11 (58) 5 (33) 9 (45) 263 Number of organs with metastases, n (%)  < 2 87 (57) 76 (54) 14 (26) 12 (19) 9 (47) 15 (79) 4 (27) 5 (25) 222  ≥ 2 65 (43) 64 (46) 40 (74) 52 (81) 10 (53) 4 (21) 11 (73) 15 (75) 261 Previous use of docetaxel, n (%)  No 139 (91) 127 (91) 48 (89) 57 (89) 16 (84) 19 (100) 13 (87) 16 (80) 435  Yes 13 (9) 13 (9) 6 (11) 7 (11) 3 (16) 0 2 (13) 4 (20) 48 Previous chemotherapy regimens, n (%)  Fluoropyrimi- 58 (38) 54 (39) 23 (43) 25 (39) 11 (58) 5 (26) 5 (33) 2 (10) 183 dine mono- therapy  Doublet chem- 83 (55) 76 (54) 28 (52) 34 (53) 6 (32) 14 (74) 9 (60) 15 (75) 265 otherapy  Triplet chemo- 11 (7) 10 (7) 3 (6) 5 (8) 2 (11) 0 1 (7) 3 (15) 35 therapy Duration of previous chemotherapy (months), n (%)  < 6 77 (51) 60 (43) 22 (41) 18 (28) 6 (32) 7 (37) 7 (47) 5 (25) 202  ≥ 6 75 (49) 80 (57) 32 (59) 46 (72) 13 (68) 12 (63) 8 (53) 15 (75) 281 Recurrence dur- 43 (28) 45 (32) 14 (26) 15 (23) 7 (37) 4 (21) 2 (13) 2 (10) 132 ing adjuvant chemotherapy Progressive 109 (72) 95 (68) 40 (74) 49 (77) 12 (63) 15 (79) 13 (87) 18 (90) 351 disease dur- ing first-line chemotherapy, n (%) Group A: patients with no detectable peritoneal lesions and no massive ascites, group B: patients with detectable peritoneal lesions and no mas- sive ascites, group C: patients with no detectable peritoneal lesions and massive ascites, group D: patients with detectable peritoneal lesions and massive ascites w-nab-PTX weekly nanoparticle-bound paclitaxel, w-sb-PTX weekly solvent-based paclitaxel 1 3 Peritoneal metastasis as a predictive factor for nab-paclitaxel in patients with pretreated… Table 2 Summary of overall survival and progression-free survival Group n OS PFS b b Median OS (months) HR (95% CI) P value Median PFS HR (95% CI) P value (95% CI) (months) (95% CI)  w-nab-PTX 152 11.6 (10.3–13.8) 1.40 (1.06–1.86) 0.018 4.9 (3.8–5.6) 1.02 (0.80–1.30) 0.888  w-sb-PTX 140 15.7 (11.9–16.9) 3.8 (3.7–4.7)  w-nab-PTX 54 12.3 (8.7–14.5) 0.64 (0.42–1.00) 0.046 6.0 (5.1–7.6) 0.62 (0.42–0.93) 0.020  w-sb-PTX 64 10.0 (9.0–11.2) 3.7 (3.5–4.1)  w-nab-PTX 19 7.4 (3.0–12.9) 0.66 (0.32–1.34) 0.245 4.5 (1.9–7.1) 0.77 (0.38–1.54) 0.448  w-sb-PTX 19 6.1 (4.3–8.6) 4.3 (2.7–5.6)  w-nab-PTX 15 7.6 (5.1–13.1) 0.47 (0.22–1.00) 0.044 4.0 (3.4–8.1) 0.43 (0.20–0.89) 0.019  w-sb-PTX 20 4.9 (2.9–6.6) 2.6 (1.7–3.8) w-nab-PTX weekly nanoparticle-bound paclitaxel, w-sb-PTX weekly solvent-based paclitaxel, OS overall survival, PFS progression-free sur- vival, HR hazard ratio Group A: patients with no detectable peritoneal lesions and no massive ascites, group B: patients with detectable peritoneal lesions and no mas- sive ascites, group C: patients with no detectable peritoneal lesions and massive ascites, group D: patients with detectable peritoneal lesions and massive ascites Log rank test metastasis based on the two categories was an accurate Differences in drug formulations between nab-PTX and reflection of peritoneal metastasis severity. sb-PTX might explain the significantly better efficacy of Furthermore, the HRs for both OS and PFS in the w-nab-PTX in patients with AGC; sb-PTX contains poly- w-nab-PTX arm compared with the w-sb-PTX arm were ethoxylated castor oil as a solvent and alcohol, whereas nab- the lowest in group D, indicating a better efficacy of PTX is a solvent-free albumin-bound form of PTX. Albumin w-nab-PTX in that group. However, the HR was the high- has a high affinity for hydrophobic drugs including PTX [4 ] est in group A, indicating poor efficacy of w-nab-PTX. and is transported across the endothelial barrier of blood Furthermore, the efficacy of w-nab-PTX in groups B and C vessels through binding to the gp60 albumin receptor and were in the middle of groups A and D, indicating good effi- activation of caveolae-mediated endothelial transcytosis cacy of w-nab-PTX in such groups. A comparison of ORR [5–7]. Simulations based on population pharmacokinetic between the w-nab-PTX and the w-sb-PTX arms showed a modeling showed that the tissue distribution of nab-PTX similar relationship among all four groups. These results was more dependent upon an active transport mechanism, suggest that the efficacy of w-nab-PTX compared with i.e., endothelial transcytosis for drug distribution into tissues w-sb-PTX may relate to peritoneal metastasis severity in than that of sb-PTX [8]. A preclinical study in rabbits, in patients with AGC. which nab-PTX and sb-PTX were intraperitoneally admin- In the treatment of patients with AGC, the presence or istered, showed that nab-PTX penetrated the peritoneum tis- absence of apparent peritoneal metastasis is important for sue better than sb-PTX [9]. Moreover, a previous preclinical selecting anti-tumor agents, particularly as second- or later- study that compared intravenous administration of nab-PTX line chemotherapy. Because of its toxicities, irinotecan is with intraperitoneal administration of sb-PTX in a peritoneal contraindicated for patients with AGC who have severe metastasis mouse model reported that intravenous nab-PTX peritoneal metastasis. We unified groups B, C, and D as demonstrated an equivalent effect of reducing ascites and the PM group. The interaction P values for OS, PFS, and peritoneal tumors to intraperitoneal sb-PTX at equal doses ORR between the PM and no PM groups were consistently [10]. Furthermore, the reduction rate of ascites in w-nab- less than 0.05 even after adjusting for background prognos- PTX was better than in w-sb-PTX (24.8 vs. 13.5%) in the tic factors. The presence or absence of apparent peritoneal ABSOLUTE trial [11] and a greater efficacy for peritoneal metastasis might be a predictive marker for selecting either metastasis would lead to longer survival. w-nab-PTX or w-sb-PTX as second-line chemotherapy for In the no PM group, although the w-nab-PTX arm patients with AGC. showed comparable PFS and ORR with the w-sb-PTX arm, 1 3 A. Takashima et al. Fig. 1 Kaplan–Meier plot of overall survival by subgroup (4-group peritoneal lesions and massive ascites, group D: patients with detect- version). Group A: patients with no detectable peritoneal lesions able peritoneal lesions and massive ascites. w-nab-PTX weekly nano- and no massive ascites, group B: patients with detectable peritoneal particle-bound paclitaxel, w-sb-PTX weekly solvent-based paclitaxel, lesions and no massive ascites, group C: patients with no detectable OS overall survival the w-sb-PTX arm showed longer OS than the w-nab-PTX biologically, although the additional analysis between arm. The median OS of w-sb-PTX (15.7 months) in this every 3 weeks nab-PTX and w-sb-PTX in the ABSOLUTE study is remarkably longer than that in other clinical trials of trial using our reclassified subgroup also suggested the second-line chemotherapy for patients with AGC, and is bet- same trend in terms of HR for OS and PFS (Supplemen- ter than studies of first-line chemotherapy for AGC, which tary Table 3). The standard second-line chemotherapy for have reported OSs ranging from 6 to 13.8 months [12–17]. AGC is the combination of ramucirumab with sb-PTX. While this favorable OS reported with w-sb-PTX may have While, phase II studies of ramucirumab with nab-PTX some bias such as hidden imbalance of other prognostic (JapicCTI-153088, NCT02317991) showed promising factors, the fact that more patients treated with w-sb-PTX activity and manageable toxicities [18]. However, it is received post-study treatment might be one of the reasons still unclear whether the results in the present study for for the difference in OS between the two arms. selecting w-nab-PTX or w-sb-PTX are applicable to the Our study had some limitations. The subgroups analysis combination with ramucirumab. Future prospective studies in this study was not pre-planned; thus, the results should of nab-PTX with ramucirumab for patients with AGC with be interpreted with caution. The mechanism causing the peritoneal metastasis/ascites are needed. The West Japan difference in efficacy for peritoneal metastasis between Oncology Group is planning a randomized trial comparing w-nab-PTX and w-sb-PTX cannot be completely explained 1 3 Peritoneal metastasis as a predictive factor for nab-paclitaxel in patients with pretreated… Fig. 2 Kaplan–Meier plot of overall survival and progression-free group the apparent peritoneal metastasis group, no PM group the no survival for the reclassified subgroup (2-group version). a Progres- apparent peritoneal metastasis group, PFS progression-free survival, sion-free survival. b Overall survival. w-nab-PTX weekly nanoparti- OS overall survival cle-bound paclitaxel, w-sb-PTX weekly solvent-based paclitaxel, PM Funding This work was supported by Taiho Pharmaceutical. No grant w-nab-PTX with ramucirumab and w-sb-PTX with ramu- numbers are applicable. cirumab for AGC with peritoneal metastasis. In conclusion, our study suggests that the presence or Compliance with ethical standards absence of apparent peritoneal metastasis might be a pre- dictive factor for selecting w-nab-PTX or w-sb-PTX in Conflict of interest KS reports personal fees from Astellas, Bristol- patients with pretreated AGC. Myers Squibb, Takeda, Pfizer, Novartis, Abbvie and Yakult, grants and personal fees from Lilly and Ono Pharma, grants from Sumitomo Acknowledgements We thank the participating patients, their families, Dainippon Pharma, MSD, Daiichi-Sankyo, Taiho Pharma and Chugai and the following site staff: Keisuke Aiba (Jikei University School of Pharma outside the submitted work. HH reports grants from AstraZen- Medicine), Yusuke Tanigawara (Keio University School of Medicine), eca, Daiichi-Sankyo, Sumitomo Dainippon Pharma, Lilly, Merck Se- and Kazuo Tamura (Fukuoka University School of Medicine) for their rono, MSD, Ono Pharma, Taiho Pharma, Chugai Pharma, Boehringer work in the Data and Safety Monitoring Committee and Yuh Sakata Ingelheim, Eisai, LSK BioPharma, Incyte and Pfizer outside the sub- (Misawa City Hospital) for medical advice. This trial was sponsored mitted work. SH reports personal fees from Lilly and Taiho Pharma by Taiho Pharmaceutical. 1 3 A. Takashima et al. outside the submitted work. KN reports grants and non-financial sup- 3. Nishina T, Boku N, Gotoh M, Shimada Y, Hamamoto Y, Yasui port from Taiho Pharma during the conduct of the study, and personal H, et al. Randomized phase II study of second-line chemotherapy fees from Taiho Pharma, Chugai Pharma, Yakult, Lilly, Ajinomoto with the best available 5-fluorouracil regimen versus weekly Pharma outside the submitted work. KA reports other from Taiho administration of paclitaxel in far advanced gastric cancer with Pharma during the conduct of the study, and other from MSD out- severe peritoneal metastases refractory to 5-fluorouracil contain- side the submitted work. KM reports grants from Ono Pharma, MSD, ing regimens (JCOG0407). Gastric Cancer. 2016;19:902–10. Daiichi-Sankyo, Kyowa Hakko Kirin, Shionogi Pharma and Gilead 4. Hawkins MJ, Soon-Shiong P, Desai N. Protein nanoparticles Sciences, and personal fees from Chugai Pharma, Taiho Pharma, as drug carriers in clinical medicine. Adv Drug Deliv Rev. Takeda, Merck Serono, Lilly and Yakult outside the submitted work. 2008;60:876–85. TE reports grants and personal fees from Lilly, Taiho Pharma, Merck 5. Schnitzer JE. gp60 is an albumin-binding glycoprotein expressed Serono and Ono Pharma, grants from Novartis, Daiichi-Sankyo, Su- by continuous endothelium involved in albumin transcytosis. Am mitomo Dainippon Pharma, AstraZeneca, Boehringer Ingelheim and J Physiol. 1992;262:246–54. MSD, and personal fees from Chugai Pharma, Nippon Kayaku and 6. Minshall RD, Tiruppathi C, Vogel SM, Niles WD, Gilchrist A, Eisai outside the submitted work. TT reports grants and personal fees Hamm HE, et al. Endothelial cell-surface gp60 activates vesicle from Taiho Pharma during the conduct of the study, and personal fees formation and trafficking via G(i)-coupled Src kinase signaling from Daiichi-Sankyo, Kyowa Hakko Kirin and Eisai, grants and per- pathway. J Cell Biol. 2000;150:1057–69. sonal fees from Chugai Pharma and Novartis, and grants from Takeda, 7. Vogel SM, Minshall RD, Pilipović M, Tiruppathi C, Malik AB. Ono Pharma, MSD and Merck Serono outside the submitted work. AS Albumin uptake and transcytosis in endothelial cells in  vivo reports personal fees from Taiho Pharma outside the submitted work. induced by albumin-binding protein. Am J Physiol Lung Cell Mol MG reports grants, personal fees and non-financial support from Taiho Physiol. 2001;281:1512–22. Pharma during the conduct of the study, grants, personal fees and non- 8. Chen N, Brachmann C, Liu X, Pierce DW, Dey J, Kerwin WS, financial support from Ono Pharma, Yakult, Chugai Pharma, Kyowa et  al. Albumin-bound nanoparticle (nab) paclitaxel exhibits Hakko Kirin and Mochida Pharma, personal fees and non-financial enhanced paclitaxel tissue distribution and tumor penetration. support from Takeda, Novartis, and Bayer outside the submitted work. Cancer Chemother Pharmacol. 2015;76:699–712. NM reports grants from Taiho Pharma during the conduct of the study, 9. Coccolini F, Acocella F, Morosi L, Brizzola S, Ghiringhelli M, and grants from Ono, MSD and Lilly outside the submitted work. NB Ceresoli M, et al. High penetration of paclitaxel in abdominal reports grants from Taiho Pharma during the conduct of the study, and wall of rabbits after hyperthermic intraperitoneal administration grants and personal fees from Taiho Pharma and Bristol-Myers Squibb of nab-paclitaxel compared to standard paclitaxel formulation. outside the submitted work. MS reports personal fees from Taiho Pharm Res. 2017;34:1180–6. Pharma outside the submitted work. SM reports personal fees from 10. Kinoshita J, Fushida S, Tsukada T, Oyama K, Watanabe T, Shoji Taiho Pharma during the conduct of the study, and personal fees from M, et al. Comparative study of the antitumor activity of Nab-pacli- Bristol-Myers Squibb outside the submitted work. WK reports grants, taxel and intraperitoneal solvent-based paclitaxel regarding peri- personal fees and non-financial support from Taiho Pharma during the toneal metastasis in gastric cancer. Oncol Rep. 2014;32:89–96. conduct of the study. All remaining authors have no conflicts of inter - 11. Hara H, Shitara K, Takashima A, Fujitani K, Koeda K, Nakayama est to declare. N, et al. Phase III trial of weekly/q3w of nab-paclitaxel vs weekly of PTX in patients with 2nd line gastric cancer treatment (ABSO- Human rights statement All procedures followed were in accordance LUTE trial). In: Plenary session at the 14th Japanese Society of with the ethical standards of the responsible committee on human Medical Oncology Annual Meeting; July 29, 2016; Yokohama, experimentation (institutional and national) and with the Helsinki Japan. Abstract a90924. Declaration of 1964 and later versions. 12. Koizumi W, Narahara H, Hara T, Takagane A, Akiya T, Takagi M, et al. S-1 plus cisplatin versus S-1 alone for first-line treatment of Informed consent All patients provided written informed consent. advanced gastric cancer (SPIRITS trial): a phase III trial. Lancet Oncol. 2008;9:215–21. 13. Boku N, Yamamoto S, Fukuda H, Shirao K, Doi T, Sawaki A, Open Access This article is distributed under the terms of the Crea- et al. Fluorouracil versus combination of irinotecan plus cisplatin tive Commons Attribution 4.0 International License (http://creat iveco versus S-1 in metastatic gastric cancer: a randomized phase 3 mmons.or g/licenses/b y/4.0/), which permits unrestricted use, distribu- study. Lancet Oncol. 2009;10:1063–69. tion, and reproduction in any medium, provided you give appropriate 14. Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, credit to the original author(s) and the source, provide a link to the Sawaki A, et al. Trastuzumab in combination with chemother- Creative Commons license, and indicate if changes were made. apy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010;376:687–97. References 15. Koizumi W, Kim YH, Fujii M, Kim HK, Imamura H, Lee KH, et al. Addition of docetaxel to S-1 without platinum prolongs sur- 1. Shitara K, Takashima A, Fujitani K, Koeda K, Hara H, Nakayama vival of patients with advanced gastric cancer: a randomized study N, et al. Nab-paclitaxel versus solvent-based paclitaxel in patients (START). J Cancer Res Clin Oncol. 2014;140:319–28. with previously treated advanced gastric cancer (ABSOLUTE): 16. Ohtsu A, Shah MA, Van Cutsem E, Rha SY, Sawaki A, Park an open-label, randomised, non-inferiority, phase 3 trial. Lancet SR, et  al. Bevacizumab in combination with chemotherapy Gastroenterol Hepatol. 2017;2:277–87. as first-line therapy in advanced gastric cancer: a randomized, 2. Imamoto H, Oba K, Sakamoto J, Iishi H, Narahara H, Yumiba double-blind, placebo-controlled phase III study. J Clin Oncol. T, et al. Assessing clinical benefit response in the treatment of 2011;29:3968–76. gastric malignant ascites with non-measurable lesions: a mul- 17. Ohtsu A, Shimada Y, Shirao K, Boku N, Hyodo I, Saito H, et al. ticenter phase II trial of paclitaxel for malignant ascites sec- Randomized phase III trial of fluorouracil alone versus fluoro - ondary to advanced/recurrent gastric cancer. Gastric Cancer. uracil plus cisplatin versus uracil and tegafur plus mitomycin in 2011;14:81–90. patients with unresectable, advanced gastric cancer: the Japan 1 3 Peritoneal metastasis as a predictive factor for nab-paclitaxel in patients with pretreated… Clinical Oncology Group Study (JCOG9205). J Clin Oncol. combination with ramucirumab in patients with previously treated 2003;21:54–9. advanced gastric cancer. Eur J Cancer. 2018;91:86–91. 18. Bando H, Shimodaira H, Fujitani K, Takashima A, Yamagu- chi K, Nakayama N, et al. A phase II study of nab-paclitaxel in Affiliations 1 2 3 4 5 6 Atsuo Takashima  · Kohei Shitara  · Kazumasa Fujitani  · Keisuke Koeda  · Hiroki Hara  · Norisuke Nakayama  · 7 8 9 10 11 12 Shuichi Hironaka  · Kazuhiro Nishikawa  · Yutaka Kimura  · Kenji Amagai  · Hirofumi Fujii  · Kei Muro  · 13 14 15 16 17 18 Taito Esaki  · Yasuhiro Choda  · Toshimi Takano  · Keisho Chin  · Atsushi Sato  · Masahiro Goto  · 19 20 21 22 1 23 Norimasa Fukushima  · Takuo Hara  · Nozomu Machida  · Manabu Ohta  · Narikazu Boku  · Masashi Shimura  · 24 25 Satoshi Morita  · Wasaburo Koizumi 1 14 Gastrointestinal Medical Oncology Division, National Department of Surgery, Hiroshima City Hiroshima Citizens Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Hospital, Hiroshima, Japan Tokyo 104-0045, Japan Department of Medical Oncology, Toranomon Hospital, Department of Gastrointestinal Oncology, National Cancer Tokyo, Japan Center Hospital East, Kashiwa, Japan Department of Gastroenterology, Cancer Institute Hospital Department of Surgery, Osaka General Medical Center, of the Japanese Foundation for Cancer Research, Tokyo, Osaka, Japan Japan 4 17 Department of Surgery, Iwate Medical University School Department of Medical Oncology, Hirosaki University of Medicine, Morioka, Japan Graduate School of Medicine, Hirosaki, Japan 5 18 Department of Gastroenterology, Saitama Cancer Center, Cancer Chemotherapy Center, Osaka Medical College Ina-machi, Japan Hospital, Takatsuki, Japan 6 19 Department of Gastroenterology, Kanagawa Cancer Center, Department of Surgery, Yamagata Prefectural Central Yokohama, Japan Hospital, Yamagata, Japan 7 20 Clinical Trial Promotion Department, Chiba Cancer Center, Department of Surgery, Kouseiren Takaoka Hospital, Chiba, Japan Takaoka, Japan 8 21 Department of Surgery, National Hospital Organization Division of Gastrointestinal Oncology, Shizuoka Cancer Osaka National Hospital, Osaka, Japan Center, Sunto-gun, Japan 9 22 Department of Surgery, Sakai City Medical Center, Sakai, Oncology Center, Hamamatsu University School Japan of Medicine, Hamamatsu, Japan 10 23 Department of Gastroenterology, Ibaraki Prefectural Central Data Science Department, Taiho Pharmaceutical. Co., Ltd., Hospital, Kasama, Japan Tokyo, Japan 11 24 Department of Clinical Oncology, Jichi Medical University Department of Biomedical Statistics and Bioinformatics, Hospital, Shimotsuke, Japan Kyoto University Graduate School of Medicine, Kyoto, Japan 12 25 Department of Clinical Oncology, Aichi Cancer Center Department of Gastroenterology, Kitasato University School Hospital, Nagoya, Japan of Medicine, Sagamihara, Japan Department of Gastrointestinal and Medical Oncology, National Kyushu Cancer Center, Fukuoka, Japan 1 3 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Gastric Cancer Springer Journals

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Medicine & Public Health; Surgical Oncology; Oncology; Abdominal Surgery; Gastroenterology; Cancer Research
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Abstract

Background In the ABSOLUTE trial, weekly nanoparticle albumin-bound paclitaxel (w-nab-PTX) showed non-inferiority to weekly solvent-based paclitaxel (w-sb-PTX) for overall survival (OS). Thus, w-nab-PTX might be an option for second- line chemotherapy in advanced gastric cancer (AGC). However, predictive factors for efficacies of these agents have not been evaluated. Methods Patients previously enrolled in the ABSOLUTE trial were divided into apparent peritoneal metastasis group (PM group) and no apparent peritoneal metastasis group (no PM group) based on baseline imaging evaluated by RECIST ver. 1.1 criteria and amount of ascites. OS, progression-free survival, and overall response rate were compared between two arms in each group. Results This study included 240 and 243 patients in the w-nab-PTX and w-sb-PTX arms, respectively. In the PM group, the w-nab-PTX arm (n = 88) had longer OS than the w-sb-PTX arm (n = 103), and median survival time (MST) of 9.9 and 8.7 months [hazard ratio (HR) 0.63; 95% CI 0.45–0.88; P = 0.0060], respectively. In the no PM group, the w-nab-PTX arm (n = 140) had shorter OS than the w-sb-PTX arm (n = 152), and MST of 11.6 and 15.7 months (HR 1.40; 95% CI 1.06–1.86; P = 0.0180), respectively. After adjusting for prognostic factors, the HR for OS in the w-nab-PTX arm versus the w-sb-PTX arm was 0.59 (95% CI 0.42–0.83; P = 0.0023; PM group) and 1.34 (95% CI 1.01–1.78; P = 0.0414; no PM group), with significant interaction between treatment efficacy and presence of peritoneal metastasis (P = 0.0003). Conclusions The presence of apparent peritoneal metastasis might be a predictive factor for selecting w-nab-PTX for pre- treated AGC patients. Trial registration number JapicCTI-132059. Keywords Peritoneal metastasis · Nab-paclitaxel · Solvent-based paclitaxel · Second-line chemotherapy · Predictive factor Introduction Solvent-based paclitaxel (sb-PTX) is one of the standard second-line chemotherapies for advanced gastric cancer (AGC). Recently, the ABSOLUTE trial compared the effi- Electronic supplementary material The online version of this cacy and safety of nanoparticle albumin-bound paclitaxel article (https ://doi.org/10.1007/s1012 0-018-0838-6) contains 2 (nab-PTX) (260  mg/m )  of every 3  weeks schedule and supplementary material, which is available to authorized users. weekly nab-PTX (100 mg/m ) (w-nab-PTX) with that of weekly sb-PTX (80 mg/m ) (w-sb-PTX) in patients with * Atsuo Takashima atakashi@ncc.go.jp AGC refractory to a fluoropyrimidine-containing chemo- therapy regimen [1]. The non-inferiority of w-nab-PTX to Extended author information available on the last page of the article Vol.:(0123456789) 1 3 A. Takashima et al. w-sb-PTX in overall survival (OS) was confirmed, while that 30 min on days 1, 8, and 15 every 4 weeks (1 cycle), while of nab-PTX (every 3 weeks) to w-sb-PTX was not. Based on those in the w-sb-PTX arm received 80 mg/m intravenous the ABSOLUTE trial results, w-nab-PTX might be an option sb-PTX over 60 min after pre-medication with steroids and for second-line chemotherapy for AGC. However, a predic-histamine H receptor antagonists on days 1, 8, and 15 every tive factor for selecting either w-sb-PTX or w-nab-PTX is 4 weeks (1 cycle). not yet available. The review board at each participating institution The peritoneum is among the most frequent metastatic approved this trial, which was conducted according to the sites of AGC. Moreover, the frequency of peritoneal metas- Declaration of Helsinki, International Conference on Har- tasis increases with the clinical course; it is more common monisation, and Good Clinical Practice. All patients pro- in pretreated patients with AGC than in chemotherapy-naïve vided written informed consent. patients. Several phase II trials showed the promising effi - cacy of w-sb-PTX for patients with AGC with peritoneal Classification of peritoneal metastasis metastasis [2, 3]. A subgroup analysis of the ABSOLUTE trial suggested that w-nab-PTX showed more favorable effi- We used two factors to classify peritoneal metastasis based cacy than w-sb-PTX in patients with peritoneal metastasis. on baseline imaging. First was the presence of detectable Furthermore, the effect of w-nab-PTX was correlated with peritoneal lesions by investigator-judged imaging, either the amount of ascites [1]. W-nab-PTX is speculated to have measurable or non-measurable according to RECIST ver. advantages over w-sb-PTX depending on the severity of 1.1, such as peritoneal nodules, thickening of the mesente- peritoneal metastasis. rium, and bowel deformity or obstruction. Second was the However, criteria for evaluating the severity of peritoneal amount of ascites evaluated by investigator-judged imaging. metastasis have not been established; neither the presence Small and large amounts of ascites were defined as “ascites of peritoneal lesions detected by imaging nor the amount limited to the pelvic cavity” and “ascites from the pelvis of ascites appropriately reflect the severity of peritoneal extending continuously to the upper abdomen”, respectively. metastasis. Some patients were diagnosed with peritoneal A moderate amount of ascites was termed “ascites other metastasis via staging laparoscopy before the initiation of than small or large ascites”. Patients were categorized as first-line chemotherapy and without peritoneal lesions or having “massive ascites” (presence of large or moderate ascites detectable by imaging before the start of second- ascites) or “no massive ascites” (presence of small ascites line chemotherapy. While some patients have ascites without or no ascites). visible peritoneal lesions such as peritoneal nodules, thick- Using these two categories, the subjects were classified ening of the mesenterium, and bowel deformity or obstruc- into four groups: group A comprised patients with no detect- tion, visible peritoneal metastasis is sometimes not associ- able peritoneal lesions and no massive ascites; group B is ated with ascites. Therefore, neither the presence of visible comprised of patients with detectable peritoneal lesions and peritoneal lesions nor ascites alone is adequate for selecting no massive ascites; group C is comprised of patients with no which regimen, w-nab-PTX or w-sb-PTX, is optimal for the detectable peritoneal lesions and massive ascites; and group patient. Moreover, the subgroup analysis of the ABSOLUTE D is comprised patients of with detectable peritoneal lesions trial was not adjusted by prognostic factors between the two and massive ascites. Furthermore, patients in groups B, C, arms. and D who had apparent peritoneal metastasis were uni- In this study, we compared the efficacy of w-nab-PTX and fied to the apparent peritoneal metastasis group (PM group), w-sb-PTX according to the severity of peritoneal metastasis while patients in group A who did not have apparent perito- based on visible peritoneal lesions and amount of ascites. neal metastasis were assigned to the no apparent peritoneal metastasis group (no PM group). Methods Statistical analysis Patients and methods The efficacy endpoints of this study were OS, progression- free survival (PFS), and overall response rate (ORR). Sur- A total of 742 patients were enrolled in the ABSOLUTE trial vival curves were estimated using the Kaplan–Meier method. between March 2013 and May 2015. We selected patients The hazard ratio (HR) and P value for OS and PFS of the allocated to the w-nab-PTX and w-sb-PTX arms, because w-nab-PTX group compared with the w-sb-PTX group were w-nab-PTX showed non-inferiority to w-sb-PTX in terms calculated using the Cox proportional hazard model. ORR of OS in the ABSOLUTE trial. The presence of peritoneal was analyzed in patients with at least one measurable lesion metastasis was a stratification factor. Patients in the w-nab- at baseline. We used Fisher’s exact test to compare the ORR PTX arm received 100 mg/m intravenous nab-PTX over between the two treatment groups and the logistic regression 1 3 Peritoneal metastasis as a predictive factor for nab-paclitaxel in patients with pretreated… model to assess the interaction for ORR among the groups. two treatment arms (median PFS: 4.9 months for w-nab-PTX To adjust the confounding factors and assess interaction and 3.8 months for w-sb-PTX; HR 1.02; 95% CI 0.80–1.30; between treatment groups (w-nab-PTX and w-sb-PTX) and P = 0.888) (Fig.  2a). In a multivariate analysis adjusting subgroups of peritoneal metastasis (peritoneal metastasis for prognostic factors, the HR for PFS of the w-nab-PTX and non-peritoneal metastasis), we used the other prognostic arm compared with the w-sb-PTX arm was 0.54 (95% CI factors as covariates such as age, performance status, histo- 0.39–0.75; P = 0.0002) in the PM group and 0.93 (95% CI logical type, previous gastrectomy, type of treatment failure 0.72–1.20; P = 0.5734) in the no PM group. The interaction with previous chemotherapy, and duration of prior chemo- for PFS after adjusting for prognostic factors was significant therapy for multivariate analysis. The confidence coefficient between the PM and no PM groups (P = 0.0191). for the confidence interval of the median time and HR for In the PM group, 52/88 (59.1%) patients treated with OS and PFS, and ORR was set to 95% (P < 0.05). All analy- w-nab-PTX and 66/103 (64.1%) patients treated with w-sb- ses were performed using SAS version 9.2. PTX received post-study treatment (P = 0.551). In the no PM group, 101/152 patients (66.4%) treated with w-nab- PTX and 111/140 patients (79.3%) treated with w-sb-PTX Results received post-study treatment (P = 0.018) (Supplementary Table 2). A total of 483 patients were analyzed in this study. Among The median OS in the PM group was 9.9 months (95% them, 240 and 243 belonged to the w-nab-PTX and w-sb- CI 7.5–12.9) and 8.7  months (95% CI 7.7–9.2) for the PTX groups, respectively. All 483 patients were included in w-nab-PTX arm and the w-sb-PTX arm (HR 0.63; 95% CI the full analysis set for the primary analysis in the ABSO- 0.45–0.88; P = 0.0060), respectively (Fig. 2b). In a multi- LUTE trial. The patient characteristics are shown in Table 1; variate analysis adjusting for prognostic factors, the HR for the classification into groups A–D is shown in Supplemen- OS of the w-nab-PTX arm compared with the w-sb-PTX tary Fig. 1. arm was 0.59 (95% CI 0.42–0.83; P = 0.0023) in the PM The OS and PFS are summarized in Table 2 and the sur- group and 1.34 (95% CI 1.01–1.78; P = 0.0414) in the no vival curves in Fig. 1. The HRs for the OS of the w-nab- PM group. The interaction for OS was significantly differ - PTX arm compared with the w-sb-PTX arm in groups A, ent between the PM and no PM groups after adjusting for B, C, and D were 1.40 (95% CI 1.06–1.86; P = 0.018), 0.64 prognostic factors (P = 0.0003). For sensitivity analysis, we (95% CI 0.42–1.00; P = 0.046), 0.66 (95% CI 0.32–1.34; added the multivariate analysis of OS and PFS to include P = 0.245), and 0.47 (95% CI 0.22–1.00; P = 0.044), respec- the imbalanced factors of sex and the number of metastatic tively. The HRs for the PFS of the w-nab-PTX arm compared organs in addition to the original covariates. The results with the w-sb-PTX arm in groups A, B, C, and D were 1.02 of the additional analysis were similar to those of analy- (95% CI 0.80–1.30; P = 0.888), 0.62 (95% CI 0.42–0.93; ses undertaken without adjusting for sex and the number of P = 0.020), 0.77 (95% CI 0.38–1.54; P = 0.448), and 0.43 metastatic organs (data not shown). (95% CI 0.20–0.89; P = 0.019), respectively. The results for the ORR are summarized in Supplementary Table 1. The ORRs were not significantly different between the w-nab- PTX and w-sb-PTX arms except in group B [45.5% (15/33) Discussion vs. 15.9% (7/44), P = 0.0057]. In the PM group, the w-nab-PTX arm showed a higher To the best of our knowledge, this study is the first to assess ORR than the w-sb-PTX arm: 40.0% (16/40) for w-nab-PTX the efficacy of w-nab-PTX and w-sb-PTX based on perito- and 16.4% (9/55) for w-sb-PTX (P = 0.0172). The ORR in neal metastasis. We showed that w-nab-PTX yielded better the no PM group was similar in the two treatment arms: OS, PFS, and ORR than w-sb-PTX in patients with apparent 30.0% (33/110) for w-nab-PTX and 28.1% (32/114) for peritoneal metastasis. w-sb-PTX (P = 0.7702). In a multivariate analysis adjusting In this study, we divided the patients into four groups for prognostic factors, the odds ratio for ORR was 3.945 using two categories, the presence of detectable perito- (95% CI 1.402–11.102; P = 0.0093) in the PM group and neal lesions by imaging and the amount of ascites. Among 1.086 (95% CI 0.593–1.991; P = 0.7890) in the no PM the four groups, group D, containing patients with both group. The interaction for ORR after adjusting for prognos- detectable peritoneal lesions and massive ascites, showed tic factors was significant (P = 0.0174). the poorest prognosis, while group A, containing patients The median PFS in the PM group was 5.7 months (95% without detectable peritoneal lesions or massive ascites, CI 4.4–7.1) and 3.7 months (95% CI 3.4–3.9) for the w-nab- showed the best prognosis. Moreover, the prognosis of PTX arm (HR 0.62; 95% CI 0.46–0.85; P = 0.0024). In the patients in groups B and C were between groups A and D. no PM group (group A), the PFS was similar between the These results suggested that our classification of peritoneal 1 3 A. Takashima et al. Table 1 Baseline characteristics of patients in the four groups Group A (N = 292) Group B (N = 118) Group C (N = 38) Group D (N = 35) Total w-nab- w-sb-PTX w-nab- w-sb-PTX w-nab- w-sb-PTX w-nab- w-sb-PTX PTX (N = 140) PTX (N = 64) PTX (N = 19) PTX (N = 20) (N = 152) (N = 54) (N = 19) (N = 15) Age (years), n (%)  < 65 58 (38) 61 (44) 22 (41) 30 (47) 7 (37) 13 (68) 8 (53) 11 (55) 210  ≥ 65 94 (62) 79 (56) 32 (59) 34 (53) 12 (63) 6 (31) 7 (47) 9 (45) 273 Sex, n (%)  Female 38 (25) 31 (22) 11 (20) 19 (30) 8 (42) 12 (63) 5 (33) 5 (25) 129  Male 114 (75) 109 (78) 43 (80) 45 (70) 11 (58) 7 (37) 10 (67) 15 (75) 354 ECOG performance status, n (%)  0 115 (76) 112 (80) 29 (54) 32 (50) 12 (63) 11 (58) 12 (80) 13 (65) 336  1 35 (23) 25 (18) 25 (46) 32 (50) 7 (37) 7 (37) 3 (20) 7 (35) 141  2 2 (1) 3 (2) 0 0 0 1 (5) 0 0 6 Histological type, n (%)  Diffuse 73 (48) 66 (47) 37 (69) 36 (56) 15 (79) 16 (84) 12 (80) 14 (70) 269  Intestinal 79 (52) 74 (53) 17 (31) 28 (44) 4 (21) 3 (16) 3 (20) 5 (25) 213  Unknown 0 0 0 0 0 0 0 1 (5) 1 Previous gastrectomy, n (%)  No 73 (48) 64 (46) 21 (39) 28 (44) 5 (26) 8 (42) 10 (67) 11 (55) 220  Yes 79 (52) 76 (54) 33 (61) 36 (56) 14 (74) 11 (58) 5 (33) 9 (45) 263 Number of organs with metastases, n (%)  < 2 87 (57) 76 (54) 14 (26) 12 (19) 9 (47) 15 (79) 4 (27) 5 (25) 222  ≥ 2 65 (43) 64 (46) 40 (74) 52 (81) 10 (53) 4 (21) 11 (73) 15 (75) 261 Previous use of docetaxel, n (%)  No 139 (91) 127 (91) 48 (89) 57 (89) 16 (84) 19 (100) 13 (87) 16 (80) 435  Yes 13 (9) 13 (9) 6 (11) 7 (11) 3 (16) 0 2 (13) 4 (20) 48 Previous chemotherapy regimens, n (%)  Fluoropyrimi- 58 (38) 54 (39) 23 (43) 25 (39) 11 (58) 5 (26) 5 (33) 2 (10) 183 dine mono- therapy  Doublet chem- 83 (55) 76 (54) 28 (52) 34 (53) 6 (32) 14 (74) 9 (60) 15 (75) 265 otherapy  Triplet chemo- 11 (7) 10 (7) 3 (6) 5 (8) 2 (11) 0 1 (7) 3 (15) 35 therapy Duration of previous chemotherapy (months), n (%)  < 6 77 (51) 60 (43) 22 (41) 18 (28) 6 (32) 7 (37) 7 (47) 5 (25) 202  ≥ 6 75 (49) 80 (57) 32 (59) 46 (72) 13 (68) 12 (63) 8 (53) 15 (75) 281 Recurrence dur- 43 (28) 45 (32) 14 (26) 15 (23) 7 (37) 4 (21) 2 (13) 2 (10) 132 ing adjuvant chemotherapy Progressive 109 (72) 95 (68) 40 (74) 49 (77) 12 (63) 15 (79) 13 (87) 18 (90) 351 disease dur- ing first-line chemotherapy, n (%) Group A: patients with no detectable peritoneal lesions and no massive ascites, group B: patients with detectable peritoneal lesions and no mas- sive ascites, group C: patients with no detectable peritoneal lesions and massive ascites, group D: patients with detectable peritoneal lesions and massive ascites w-nab-PTX weekly nanoparticle-bound paclitaxel, w-sb-PTX weekly solvent-based paclitaxel 1 3 Peritoneal metastasis as a predictive factor for nab-paclitaxel in patients with pretreated… Table 2 Summary of overall survival and progression-free survival Group n OS PFS b b Median OS (months) HR (95% CI) P value Median PFS HR (95% CI) P value (95% CI) (months) (95% CI)  w-nab-PTX 152 11.6 (10.3–13.8) 1.40 (1.06–1.86) 0.018 4.9 (3.8–5.6) 1.02 (0.80–1.30) 0.888  w-sb-PTX 140 15.7 (11.9–16.9) 3.8 (3.7–4.7)  w-nab-PTX 54 12.3 (8.7–14.5) 0.64 (0.42–1.00) 0.046 6.0 (5.1–7.6) 0.62 (0.42–0.93) 0.020  w-sb-PTX 64 10.0 (9.0–11.2) 3.7 (3.5–4.1)  w-nab-PTX 19 7.4 (3.0–12.9) 0.66 (0.32–1.34) 0.245 4.5 (1.9–7.1) 0.77 (0.38–1.54) 0.448  w-sb-PTX 19 6.1 (4.3–8.6) 4.3 (2.7–5.6)  w-nab-PTX 15 7.6 (5.1–13.1) 0.47 (0.22–1.00) 0.044 4.0 (3.4–8.1) 0.43 (0.20–0.89) 0.019  w-sb-PTX 20 4.9 (2.9–6.6) 2.6 (1.7–3.8) w-nab-PTX weekly nanoparticle-bound paclitaxel, w-sb-PTX weekly solvent-based paclitaxel, OS overall survival, PFS progression-free sur- vival, HR hazard ratio Group A: patients with no detectable peritoneal lesions and no massive ascites, group B: patients with detectable peritoneal lesions and no mas- sive ascites, group C: patients with no detectable peritoneal lesions and massive ascites, group D: patients with detectable peritoneal lesions and massive ascites Log rank test metastasis based on the two categories was an accurate Differences in drug formulations between nab-PTX and reflection of peritoneal metastasis severity. sb-PTX might explain the significantly better efficacy of Furthermore, the HRs for both OS and PFS in the w-nab-PTX in patients with AGC; sb-PTX contains poly- w-nab-PTX arm compared with the w-sb-PTX arm were ethoxylated castor oil as a solvent and alcohol, whereas nab- the lowest in group D, indicating a better efficacy of PTX is a solvent-free albumin-bound form of PTX. Albumin w-nab-PTX in that group. However, the HR was the high- has a high affinity for hydrophobic drugs including PTX [4 ] est in group A, indicating poor efficacy of w-nab-PTX. and is transported across the endothelial barrier of blood Furthermore, the efficacy of w-nab-PTX in groups B and C vessels through binding to the gp60 albumin receptor and were in the middle of groups A and D, indicating good effi- activation of caveolae-mediated endothelial transcytosis cacy of w-nab-PTX in such groups. A comparison of ORR [5–7]. Simulations based on population pharmacokinetic between the w-nab-PTX and the w-sb-PTX arms showed a modeling showed that the tissue distribution of nab-PTX similar relationship among all four groups. These results was more dependent upon an active transport mechanism, suggest that the efficacy of w-nab-PTX compared with i.e., endothelial transcytosis for drug distribution into tissues w-sb-PTX may relate to peritoneal metastasis severity in than that of sb-PTX [8]. A preclinical study in rabbits, in patients with AGC. which nab-PTX and sb-PTX were intraperitoneally admin- In the treatment of patients with AGC, the presence or istered, showed that nab-PTX penetrated the peritoneum tis- absence of apparent peritoneal metastasis is important for sue better than sb-PTX [9]. Moreover, a previous preclinical selecting anti-tumor agents, particularly as second- or later- study that compared intravenous administration of nab-PTX line chemotherapy. Because of its toxicities, irinotecan is with intraperitoneal administration of sb-PTX in a peritoneal contraindicated for patients with AGC who have severe metastasis mouse model reported that intravenous nab-PTX peritoneal metastasis. We unified groups B, C, and D as demonstrated an equivalent effect of reducing ascites and the PM group. The interaction P values for OS, PFS, and peritoneal tumors to intraperitoneal sb-PTX at equal doses ORR between the PM and no PM groups were consistently [10]. Furthermore, the reduction rate of ascites in w-nab- less than 0.05 even after adjusting for background prognos- PTX was better than in w-sb-PTX (24.8 vs. 13.5%) in the tic factors. The presence or absence of apparent peritoneal ABSOLUTE trial [11] and a greater efficacy for peritoneal metastasis might be a predictive marker for selecting either metastasis would lead to longer survival. w-nab-PTX or w-sb-PTX as second-line chemotherapy for In the no PM group, although the w-nab-PTX arm patients with AGC. showed comparable PFS and ORR with the w-sb-PTX arm, 1 3 A. Takashima et al. Fig. 1 Kaplan–Meier plot of overall survival by subgroup (4-group peritoneal lesions and massive ascites, group D: patients with detect- version). Group A: patients with no detectable peritoneal lesions able peritoneal lesions and massive ascites. w-nab-PTX weekly nano- and no massive ascites, group B: patients with detectable peritoneal particle-bound paclitaxel, w-sb-PTX weekly solvent-based paclitaxel, lesions and no massive ascites, group C: patients with no detectable OS overall survival the w-sb-PTX arm showed longer OS than the w-nab-PTX biologically, although the additional analysis between arm. The median OS of w-sb-PTX (15.7 months) in this every 3 weeks nab-PTX and w-sb-PTX in the ABSOLUTE study is remarkably longer than that in other clinical trials of trial using our reclassified subgroup also suggested the second-line chemotherapy for patients with AGC, and is bet- same trend in terms of HR for OS and PFS (Supplemen- ter than studies of first-line chemotherapy for AGC, which tary Table 3). The standard second-line chemotherapy for have reported OSs ranging from 6 to 13.8 months [12–17]. AGC is the combination of ramucirumab with sb-PTX. While this favorable OS reported with w-sb-PTX may have While, phase II studies of ramucirumab with nab-PTX some bias such as hidden imbalance of other prognostic (JapicCTI-153088, NCT02317991) showed promising factors, the fact that more patients treated with w-sb-PTX activity and manageable toxicities [18]. However, it is received post-study treatment might be one of the reasons still unclear whether the results in the present study for for the difference in OS between the two arms. selecting w-nab-PTX or w-sb-PTX are applicable to the Our study had some limitations. The subgroups analysis combination with ramucirumab. Future prospective studies in this study was not pre-planned; thus, the results should of nab-PTX with ramucirumab for patients with AGC with be interpreted with caution. The mechanism causing the peritoneal metastasis/ascites are needed. The West Japan difference in efficacy for peritoneal metastasis between Oncology Group is planning a randomized trial comparing w-nab-PTX and w-sb-PTX cannot be completely explained 1 3 Peritoneal metastasis as a predictive factor for nab-paclitaxel in patients with pretreated… Fig. 2 Kaplan–Meier plot of overall survival and progression-free group the apparent peritoneal metastasis group, no PM group the no survival for the reclassified subgroup (2-group version). a Progres- apparent peritoneal metastasis group, PFS progression-free survival, sion-free survival. b Overall survival. w-nab-PTX weekly nanoparti- OS overall survival cle-bound paclitaxel, w-sb-PTX weekly solvent-based paclitaxel, PM Funding This work was supported by Taiho Pharmaceutical. No grant w-nab-PTX with ramucirumab and w-sb-PTX with ramu- numbers are applicable. cirumab for AGC with peritoneal metastasis. In conclusion, our study suggests that the presence or Compliance with ethical standards absence of apparent peritoneal metastasis might be a pre- dictive factor for selecting w-nab-PTX or w-sb-PTX in Conflict of interest KS reports personal fees from Astellas, Bristol- patients with pretreated AGC. Myers Squibb, Takeda, Pfizer, Novartis, Abbvie and Yakult, grants and personal fees from Lilly and Ono Pharma, grants from Sumitomo Acknowledgements We thank the participating patients, their families, Dainippon Pharma, MSD, Daiichi-Sankyo, Taiho Pharma and Chugai and the following site staff: Keisuke Aiba (Jikei University School of Pharma outside the submitted work. HH reports grants from AstraZen- Medicine), Yusuke Tanigawara (Keio University School of Medicine), eca, Daiichi-Sankyo, Sumitomo Dainippon Pharma, Lilly, Merck Se- and Kazuo Tamura (Fukuoka University School of Medicine) for their rono, MSD, Ono Pharma, Taiho Pharma, Chugai Pharma, Boehringer work in the Data and Safety Monitoring Committee and Yuh Sakata Ingelheim, Eisai, LSK BioPharma, Incyte and Pfizer outside the sub- (Misawa City Hospital) for medical advice. This trial was sponsored mitted work. SH reports personal fees from Lilly and Taiho Pharma by Taiho Pharmaceutical. 1 3 A. Takashima et al. outside the submitted work. KN reports grants and non-financial sup- 3. Nishina T, Boku N, Gotoh M, Shimada Y, Hamamoto Y, Yasui port from Taiho Pharma during the conduct of the study, and personal H, et al. Randomized phase II study of second-line chemotherapy fees from Taiho Pharma, Chugai Pharma, Yakult, Lilly, Ajinomoto with the best available 5-fluorouracil regimen versus weekly Pharma outside the submitted work. KA reports other from Taiho administration of paclitaxel in far advanced gastric cancer with Pharma during the conduct of the study, and other from MSD out- severe peritoneal metastases refractory to 5-fluorouracil contain- side the submitted work. KM reports grants from Ono Pharma, MSD, ing regimens (JCOG0407). Gastric Cancer. 2016;19:902–10. Daiichi-Sankyo, Kyowa Hakko Kirin, Shionogi Pharma and Gilead 4. Hawkins MJ, Soon-Shiong P, Desai N. Protein nanoparticles Sciences, and personal fees from Chugai Pharma, Taiho Pharma, as drug carriers in clinical medicine. Adv Drug Deliv Rev. Takeda, Merck Serono, Lilly and Yakult outside the submitted work. 2008;60:876–85. TE reports grants and personal fees from Lilly, Taiho Pharma, Merck 5. Schnitzer JE. gp60 is an albumin-binding glycoprotein expressed Serono and Ono Pharma, grants from Novartis, Daiichi-Sankyo, Su- by continuous endothelium involved in albumin transcytosis. Am mitomo Dainippon Pharma, AstraZeneca, Boehringer Ingelheim and J Physiol. 1992;262:246–54. MSD, and personal fees from Chugai Pharma, Nippon Kayaku and 6. Minshall RD, Tiruppathi C, Vogel SM, Niles WD, Gilchrist A, Eisai outside the submitted work. TT reports grants and personal fees Hamm HE, et al. Endothelial cell-surface gp60 activates vesicle from Taiho Pharma during the conduct of the study, and personal fees formation and trafficking via G(i)-coupled Src kinase signaling from Daiichi-Sankyo, Kyowa Hakko Kirin and Eisai, grants and per- pathway. J Cell Biol. 2000;150:1057–69. sonal fees from Chugai Pharma and Novartis, and grants from Takeda, 7. Vogel SM, Minshall RD, Pilipović M, Tiruppathi C, Malik AB. Ono Pharma, MSD and Merck Serono outside the submitted work. AS Albumin uptake and transcytosis in endothelial cells in  vivo reports personal fees from Taiho Pharma outside the submitted work. induced by albumin-binding protein. Am J Physiol Lung Cell Mol MG reports grants, personal fees and non-financial support from Taiho Physiol. 2001;281:1512–22. Pharma during the conduct of the study, grants, personal fees and non- 8. Chen N, Brachmann C, Liu X, Pierce DW, Dey J, Kerwin WS, financial support from Ono Pharma, Yakult, Chugai Pharma, Kyowa et  al. Albumin-bound nanoparticle (nab) paclitaxel exhibits Hakko Kirin and Mochida Pharma, personal fees and non-financial enhanced paclitaxel tissue distribution and tumor penetration. support from Takeda, Novartis, and Bayer outside the submitted work. Cancer Chemother Pharmacol. 2015;76:699–712. NM reports grants from Taiho Pharma during the conduct of the study, 9. Coccolini F, Acocella F, Morosi L, Brizzola S, Ghiringhelli M, and grants from Ono, MSD and Lilly outside the submitted work. NB Ceresoli M, et al. High penetration of paclitaxel in abdominal reports grants from Taiho Pharma during the conduct of the study, and wall of rabbits after hyperthermic intraperitoneal administration grants and personal fees from Taiho Pharma and Bristol-Myers Squibb of nab-paclitaxel compared to standard paclitaxel formulation. outside the submitted work. MS reports personal fees from Taiho Pharm Res. 2017;34:1180–6. Pharma outside the submitted work. SM reports personal fees from 10. Kinoshita J, Fushida S, Tsukada T, Oyama K, Watanabe T, Shoji Taiho Pharma during the conduct of the study, and personal fees from M, et al. Comparative study of the antitumor activity of Nab-pacli- Bristol-Myers Squibb outside the submitted work. WK reports grants, taxel and intraperitoneal solvent-based paclitaxel regarding peri- personal fees and non-financial support from Taiho Pharma during the toneal metastasis in gastric cancer. Oncol Rep. 2014;32:89–96. conduct of the study. All remaining authors have no conflicts of inter - 11. Hara H, Shitara K, Takashima A, Fujitani K, Koeda K, Nakayama est to declare. N, et al. Phase III trial of weekly/q3w of nab-paclitaxel vs weekly of PTX in patients with 2nd line gastric cancer treatment (ABSO- Human rights statement All procedures followed were in accordance LUTE trial). In: Plenary session at the 14th Japanese Society of with the ethical standards of the responsible committee on human Medical Oncology Annual Meeting; July 29, 2016; Yokohama, experimentation (institutional and national) and with the Helsinki Japan. Abstract a90924. Declaration of 1964 and later versions. 12. Koizumi W, Narahara H, Hara T, Takagane A, Akiya T, Takagi M, et al. S-1 plus cisplatin versus S-1 alone for first-line treatment of Informed consent All patients provided written informed consent. advanced gastric cancer (SPIRITS trial): a phase III trial. Lancet Oncol. 2008;9:215–21. 13. 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Koizumi W, Kim YH, Fujii M, Kim HK, Imamura H, Lee KH, et al. Addition of docetaxel to S-1 without platinum prolongs sur- 1. Shitara K, Takashima A, Fujitani K, Koeda K, Hara H, Nakayama vival of patients with advanced gastric cancer: a randomized study N, et al. Nab-paclitaxel versus solvent-based paclitaxel in patients (START). J Cancer Res Clin Oncol. 2014;140:319–28. with previously treated advanced gastric cancer (ABSOLUTE): 16. Ohtsu A, Shah MA, Van Cutsem E, Rha SY, Sawaki A, Park an open-label, randomised, non-inferiority, phase 3 trial. Lancet SR, et  al. Bevacizumab in combination with chemotherapy Gastroenterol Hepatol. 2017;2:277–87. as first-line therapy in advanced gastric cancer: a randomized, 2. Imamoto H, Oba K, Sakamoto J, Iishi H, Narahara H, Yumiba double-blind, placebo-controlled phase III study. J Clin Oncol. T, et al. Assessing clinical benefit response in the treatment of 2011;29:3968–76. gastric malignant ascites with non-measurable lesions: a mul- 17. 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A phase II study of nab-paclitaxel in Affiliations 1 2 3 4 5 6 Atsuo Takashima  · Kohei Shitara  · Kazumasa Fujitani  · Keisuke Koeda  · Hiroki Hara  · Norisuke Nakayama  · 7 8 9 10 11 12 Shuichi Hironaka  · Kazuhiro Nishikawa  · Yutaka Kimura  · Kenji Amagai  · Hirofumi Fujii  · Kei Muro  · 13 14 15 16 17 18 Taito Esaki  · Yasuhiro Choda  · Toshimi Takano  · Keisho Chin  · Atsushi Sato  · Masahiro Goto  · 19 20 21 22 1 23 Norimasa Fukushima  · Takuo Hara  · Nozomu Machida  · Manabu Ohta  · Narikazu Boku  · Masashi Shimura  · 24 25 Satoshi Morita  · Wasaburo Koizumi 1 14 Gastrointestinal Medical Oncology Division, National Department of Surgery, Hiroshima City Hiroshima Citizens Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Hospital, Hiroshima, Japan Tokyo 104-0045, Japan Department of Medical Oncology, Toranomon Hospital, Department of Gastrointestinal Oncology, National Cancer Tokyo, Japan Center Hospital East, Kashiwa, Japan Department of Gastroenterology, Cancer Institute Hospital Department of Surgery, Osaka General Medical Center, of the Japanese Foundation for Cancer Research, Tokyo, Osaka, Japan Japan 4 17 Department of Surgery, Iwate Medical University School Department of Medical Oncology, Hirosaki University of Medicine, Morioka, Japan Graduate School of Medicine, Hirosaki, Japan 5 18 Department of Gastroenterology, Saitama Cancer Center, Cancer Chemotherapy Center, Osaka Medical College Ina-machi, Japan Hospital, Takatsuki, Japan 6 19 Department of Gastroenterology, Kanagawa Cancer Center, Department of Surgery, Yamagata Prefectural Central Yokohama, Japan Hospital, Yamagata, Japan 7 20 Clinical Trial Promotion Department, Chiba Cancer Center, Department of Surgery, Kouseiren Takaoka Hospital, Chiba, Japan Takaoka, Japan 8 21 Department of Surgery, National Hospital Organization Division of Gastrointestinal Oncology, Shizuoka Cancer Osaka National Hospital, Osaka, Japan Center, Sunto-gun, Japan 9 22 Department of Surgery, Sakai City Medical Center, Sakai, Oncology Center, Hamamatsu University School Japan of Medicine, Hamamatsu, Japan 10 23 Department of Gastroenterology, Ibaraki Prefectural Central Data Science Department, Taiho Pharmaceutical. Co., Ltd., Hospital, Kasama, Japan Tokyo, Japan 11 24 Department of Clinical Oncology, Jichi Medical University Department of Biomedical Statistics and Bioinformatics, Hospital, Shimotsuke, Japan Kyoto University Graduate School of Medicine, Kyoto, Japan 12 25 Department of Clinical Oncology, Aichi Cancer Center Department of Gastroenterology, Kitasato University School Hospital, Nagoya, Japan of Medicine, Sagamihara, Japan Department of Gastrointestinal and Medical Oncology, National Kyushu Cancer Center, Fukuoka, Japan 1 3

Journal

Gastric CancerSpringer Journals

Published: May 31, 2018

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