Background

Delta-like ligand 4 (DLL4) is a ligand that activates the Notch pathway which is important for cancer stem cell (CSC) survival. Demcizumab is a humanized, anti-DLL4 antibody that has been shown using an in vivo tumorigenicity limiting dilution assay to inhibit tumor growth and decrease CSC frequency in minimally passaged human xenograft models. In addition, inhibition of DLL4 has also been shown in preclinical studies to cause dysfunctional sprouting of new vessels resulting in an antiangiogenic effect. Encouraging data from a Phase 1b study of paclitaxel protein-bound particles for injectable suspension (Abraxane^®), gemcitabine and demcizumab in patients with 1st line metastatic pancreatic cancer led to this double blind randomized 3 arm placebo-controlled Phase 2 study.

Methods

Patients with metastatic pancreatic cancer were randomized (1:1:1) to 1st-line therapy with either Arm 1 - GAP, Arm 2 - GAD with a single 70 day truncated course of demcizumab or Arm 3 - GAD with two 70 day truncated courses of demcizumab (second course starting on Day 168). GA were given at usual dose & schedule, P/D was given IV on days 1 and 15 in cycles 1-3 & 7-9. The primary endpoint was progression-free survival and secondary endpoints included response, survival, safety, immunogenicity, pharmacokinetics, and biomarkers of Notch signaling and CSCs in blood, hair follicles and tumor cells. The primary study analyses compared GAP to the two pooled GAD arms.

Results

207 patients were randomized and 204 were treated. The median age was 63, the male/female ratio was 116/88, the ECOG 0 vs 1 distribution was 98/106, the median # metastatic sites was 2 and 74% had hepatic metastases. The response/clinical benefit rates were 41.2%/70.6% and 33.1%/74.3% in the GAP and pooled GAD arms, respectively. The median progression-free survival (PFS) (mPFS) was 5.5 months in the GAP and pooled GAD arms. The interim median overall survival (OS) for the GAP and pooled GAD arms were not reached and 13.2 months (HR = 1.02), respectively. Geographic differences in OS were observed. GAD was generally well tolerated with nausea, diarrhea, anemia, peripheral edema and fatigue being the most common reported toxicities. The incidence of the Grade 3 or greater toxicities of special interest with demcizumab therapy were hypertension (7.4% vs 16.2%), pulmonary hypertension (0% vs 0.7%), heart failure (0% vs. 3.7%), and bleeding (1.5% vs. 8.1%) in the GAP and pooled GAD arms, respectively. No cases of Grade 3 heart failure or pulmonary hypertension occurred during the 2nd 70 day course of demcizumab.

Conclusions

The addition of either 1 or 2 truncated courses of demcizumab to 1^st-line gemcitabine and Abraxane did not improve the efficacy compared to GAP in patients with 1^st line metastatic pancreatic cancer. GAD therapy was generally well tolerated.

Clinical trial identification

NCT02289898 - November 10, 2014

Legal entity responsible for the study

OncoMed Pharmaceuticals

Funding

OncoMed Pharmaceuticals

Disclosure

R. Stagg: Employee and own stock of OncoMed. All other authors have declared no conflicts of interest.

Background

L-asparaginase (L-ASP) hydrolyses asparagine, an amino acid essential for the survival and proliferation of cancer cells. Asparagine synthetase (ASNS) expression is believed to play a role in determining sensitivity to asparaginase treatment. Eryaspase, L-ASP encapsulated in erythrocytes, showed encouraging activity and improved safety profile compared to L-ASP in patients (pts) with relapsed ALL. This prompted us to evaluate eryaspase in combination with chemo in pancreatic cancer (PC).

Methods

This open label, multicenter phase 2b randomized study (2:1) enrolled pts with second-line metastatic PC. Pts eligible to gemcitabine or FOLFOX regimen were randomized to chemo +/- eryaspase (100 IU/Kg D3 and D17 of 4-wk regimen) until disease progression. The endpoint of the study was improvement in PFS or OS in pts with no or low ASNS (0/1) expression as determined by IHC, with a target Hazard ratio (HR) < 0.85. Secondary endpoints included OS, PFS, ORR, safety and QoL. The primary analysis took place after around 6 mo follow-up (FUP).

Results

140 pts were enrolled. The baseline characteristics were well balanced across the 2 treatment arms. The ASNS 0/1 (n = 65 and 32 in eryaspase & control arms, respectively), demonstrated a HR of 0.73 for PFS and 0.62 for OS; therefore the trial met its primary endpoint. In the entire patient population, eryaspase led to improvement of OS (median 26.1 wks) compared to control (median 19 wks); HR of 0.57 (P = 0.03). Similarly, eryaspase led to significant improvement in PFS. The treatment effect in favor of eryaspase was comparable across various prognostic indicators. Overall, treatment was well tolerated, with asthenia, nausea and vomiting, and myelosuppression being the most frequent events in both arms. Final results with additional FUP on efficacy and safety outcome measures will be provided at the meeting.

Conclusions

In pts with PC receiving second-line chemotherapy treatment, the addition of eryaspase provided significant improvement in OS and PFS, irrespective of ASNS expression levels. The role of the ASNS expression will be further investigated. Further investigation of eryaspase in PC in a P3 study is warranted.

Clinical trial identification

2013-004262-34

Legal entity responsible for the study

Erytech Pharma

Funding

Erytech Pharma

Disclosure

P. Hammel: Advisory board: Astra Zeneca; Merck Serono, Celgene, Shire, Ipsen. Corporate-sponsored research: Roche, Celgene. L. Mineur: Advisory board: Sanofi, Bayer and Roche. C. Louvet: Advisory board: Celgene and Roche. D. Tougeron: Advisory board: Sanofi, Amgen and Celgene. W. Berlier, A. Gupta: Employee pf Erytech Pharma. T. André: Advisory board: BMS, Amgen and Roche. I. El-Hariry: Employee as Chief Medical Officer, own stocks, Board of Directors: Erytech Pharma. All other authors have declared no conflicts of interest.

Background

Treatment options for pts with LAPC are limited. In the phase 3 MPACT trial, nab-P + G treatment (Tx) resulted in a > 3-fold reduction in primary pancreatic tumor burden vs G in pts with metastatic PC, suggesting that the regimen may be effective in LAPC. Interim efficacy and safety results from the international, multicenter, prospective phase 2 LAPACT trial are presented.

Methods

During induction, treatment-naive pts with unresectable LAPC and ECOG PS ≤ 1 received 6 cycles of nab-P 125 mg/m² + G 1000 mg/m² on D 1, 8, and 15 of each 28-day cycle. After induction, pts without PD or unacceptable AEs were eligible for the investigator’s choice (IC) of continued Tx with nab-P + G, chemoradiation (CRT), or surgery. Surgery could occur prior to completing 6 cycles if the investigator deemed a sufficient tumor response. The primary endpoint was TTF. A secondary endpoint was disease control rate (DCR = CR, PR, and SD [≥ 16 weeks]) in pts who completed induction and had ≥ 1 postbaseline assessment. Data for pts who received their first dose of Tx by Oct 1, 2016 are reported.

Results

A total of 101 pts with LAPC received nab-P + G induction. Median age was 65 years (range, 42-85), and median time from primary diagnosis to first dose was 27 days. Pts received a median of 5 Tx cycles (range, 1-6). A total of 60 patients (59%) completed induction. Among 93 evaluable patients, the DCR was 82% (76/93; PR, n = 33; SD ≥ 16 wks, n = 43); 12 pts had SD < 16 wks, and 5 pts (5%) had PD. The most frequent reasons for discontinuation during induction (n = 101 evaluable) were AEs (18%), PD (7%), and physician decision (5%). The 2 most common grade ≥ 3 AEs were neutropenia (37%) and anemia (9%). Grade ≥ 3 peripheral sensory neuropathy was reported in 4% of pts. After completion of induction, 42 patients received protocol-specific IC therapy: 13 continued nab-P + G, 15 received CRT, and 14 underwent surgery (R0, n = 4; R1, n = 6; R2, n = 1; 3 missing; resection conversion rate = 33%).

Conclusions

The reported DCR of 82% and PR rate of 35% for nab-P + G are promising, and there were no new safety signals compared with previous studies. These interim results suggest that nab-P + G is an appropriate LAPC Tx. NCT02301143.

Clinical trial identification

NCT02301143

Legal entity responsible for the study

Celgene Corporation

Funding

Celgene Corporation

Disclosure

P.A. Philip: Research funding: Celgene, Bayer, Incyte; consultant or advisory role: Celgene; speakers’ bureau: Bayer, Roche, Sanofi, Amgen. J. Lacy, C. Borg: Research funding: Celgene. A. Sobrero: Honoraria: Bayer, Celgene, Merck, Roche, Sanofi. Consulting or advisory role: Amgen, Bayer, Merck, Pfizer; speaker’s bureau: Amgen, BMS, Merck, Sanofi. E.S. Kim: Honoraria, speaker’s bureau, advisory board: GuardantHealth; consultant: Pharmacyclics, Medallion Healthcare; advisory board: Bayer; consultant: Momenta. S. Dowden: Honoraria, advisory role, speaker’s bureau, Amgen, Bayer, Celgene, Lilly, Roche A. Zakari: Speakers bureau, Amgen, Celgene. F. Rivera Herrero: Research funding, Celgene, Bayer, Roche, Amgen, Merck-Serono, MSD, Sanofi, Lilly; consultant or advisory role, Celgene, Bayer, Roche, Amgen, Merck-Serono, MSD, Sanofi, Lilly; speaker’s bureau, Celgene, Bayer, Roche, Sanofi, Amgen, Lilly. J. Shiansong Li, T.J. Ong, T. Nydam: Employment, stock ownership: Celgene. P. Hammel: Consultant or advisory role, honoraria, travel accommodations, expenses: Celgene. All other authors have declared no conflicts of interest.

Background

Nab-P+G significantly improved overall survival versus G in Patients (P) with Karnofsky index ≥70% metastatic PDAC (Von Hoff et al, 2013). The aim of this study was to select a tolerable dose -schedule of nab-P+G (Ph I), and to evaluate the efficacy of the selected regimen (Ph II) in patients with previously untreated ECOG-2 advanced PDAC.

Methods

In the phase1 portion of the study patients were randomized to one of 4 treatment regimens including G 1000 mg/m² and nab-P 150 mg/m² (arm B) or 125 mg/m² (arm D) days 1 and 15 every 28 days or same dose of G and nab-P 100 mg/m² (arm C) or 125 mg/m² (arm E) days 1, 8, and 15 every 28 days. The two safest regimens determined by analyzing hematological and non-hematological grade 3-4 toxicity, 30 and 60 days mortality, treatment discontinuation due to toxicity and dose intensity were selected for evaluation in the phase 2 portion of the study with 6 months overall survival (OS) as the primary endpoint.

Results

Regimens arm C and arm E (days 1, 8, 15 every 28 days schedule) were selected for the phase 2 portion of the study. A total of 221 patients (111 in arm C/110 in arm E) were enrolled. Median age was 71/68 y, 51/55% were male and 91/83% had metastatic disease (liver 63/62%). Most frequent grade 3-4 toxicity per arm were anemia (12/7%), neutropenia (32/30%), thrombocytopenia (7/11%), febrile neutropenia (3/4%), asthenia (14/16%) and neurotoxicity (11/16%). There were no significant differences in 6 months OS 63/69%, response rate (RR) 24/28% and median progression free survival (PFS) 5.7/6.7 months respectively in each arm.

Conclusions

Nab-P in combination with G, both at 100 and 125 mg/m² dose administered on a standard schedule of days 1, 8 and 15 is well tolerated and results in acceptable OS, RR and PFS in this fragile patient population.

Clinical trial identification

NCT02382263 EudraCT: 2012-003605-97

Legal entity responsible for the study

PH Research

Funding

Celgene

Disclosure

M. Hidalgo: Honoraria: Celgene. Consulting or advisory role: Celgene. Research funding: Celgene. Travel, accomodations: Celgene. R. Pazo-Cid: Consulting or advisory role: Celgene, Baxalta. A. Muñoz: Consulting or advisory role: Celgene. J. Sastre: Consulting or advisory role: Amgen, Sanofi, Bayer, Boheringer. Travel accomodations: Merck. Researcha funding: Amgen, Merck. All other authors have declared no conflicts of interest.

Background

Stage IV pancreatic cancer is a lethal disease. Current standard practice is combination chemotherapy such as FOLFIRINOX or Gemcitabine and Abraxane. The glycolic and mitochondrial metabolism are aberrant in pancreatic cancer and translate into chemoresistance. Inhibition of glutamine metabolism can potentially synergize with therapies that increase intracellular reactive oxygen species such as FOLFIRINOX components. CPI- 613 is a novel antimitocondrial developed by Rafael Pharmaceuticals that showed preclinical activity in pancreatic cancer.

Methods

We designed a phase 1 study to evaluate for synergy between CPI -613 and FOLFIRINOX for patients with stage IV pancreatic cancer. Aims: To determine the maximum tolerated dose (MTD) of CPI- 613 when used in combination with modified FOLFIRINOX. To assess the safety of CPI-613 + modified FOLFIRINOX To obtain preliminary data on efficacy of treatment.

Results

Updated Results as of July, 2017 Toxicity: No deaths due to adverse events were reported. The MTD was identified at 500 mg/m² and a total of 18 patients were treated at the MTD. The most common grade 3–4 non-hematological adverse events: hyperglycemia, hypokalemia, peripheral sensory neuropathy, diarrhea, and abdominal pain. The most common grade 3–4 hematological adverse events: neutropenia, lymphopenia, anemia and thrombocytopenia Preliminary efficacy: Of the 18 patients treated at MTD– 8 patients are alive and 3 patients are still on treatment. The median PFS is 10.4 months, 95% CI (119 to 560 days) – 3 patients are still alive and on treatment who have not progressed. Median overall survival is 20.1 months, data still maturing. The 95% CI cannot be accurately estimated yet. Three patients achieved a complete response.

Conclusions

CPI-613 is a first in class non-redox active lipoate derivative being tested in phase I clinical trial in combination with FOLFIRINOX. The MTD for CPI-613 was identified at 500mg/m². The treatment combination is feasible and well-tolerated. The response rate was 61%, which is higher than FOLFIRINOX alone (31.6%). The median PFS is 10.4months and the median OS is 20.1 months, data still maturing. A randomized, international phase 3 study of FOLFIRINOX vs. m FOLFIRINOX+ CPI613 will open in 2018.

Clinical trial identification

NCT01835041, First received: April 16, 2013 Last updated: May 30, 2017 Last verified: May 2017

Legal entity responsible for the study

Wake Forest University, School of Medicine

Funding

Cornerstone Pharmaceutical now Rafael Pharmaceuticals

Disclosure

T. Pardee: Chief Medical Officer and employee of Rafael Pharmaceutical (name change on June 5th 2017 from Cornerstone Pharmaceutical). Dr Pardee has no stock or equity in the company. S. Luther: Employee of Rafael Pharmaceuticals and the COO of the company. He owns stock in the company. All other authors have declared no conflicts of interest.

Background

Pancreatic ductal adenocarcinomas (PDAC) exhibit a high degree of desmoplasia, with extensive connective tissue growth factor (CTGF) expression and extracellular matrix production^{1, 2}. Pamrevlumab (FG-3019), anti-CTGF antibody, is evaluated in fibrotic disease and cancer. Studies in the LSL-Kras^G12D/+; LSL-Trp53^R172H/+; Pdx-1-Cre (KPC) transgenic mouse model of PDAC demonstrated that pamrevlumab, in combination with gemcitabine, prolonged survival and increased tumor cell apoptosis associated with the down-regulation of the anti-apoptotic protein XIAP³.

Methods

In Phase 2 randomized study, gemcitabine/Nab-paclitaxel (G/N) +/- pamrevlumab was given to treatment-naïve locally advanced pancreatic cancer (LAPC) patients to improve resection outcomes and overall survival (OS). 33 LAPC patients were randomized 2:1 to G/N with (Arm A) (n = 22) or without (Arm B) (n = 11) pamrevlumab. Patients who completed 6 cycles of chemotherapy underwent resectability assessment by NCCN and other (CA 19-9, PET, RECIST) criteria, and, if eligible, resection with no further treatment. Patients who progressed received second-line treatment as per physician choice.

Results

No increases in SAEs or surgical complications were observed in Arm A vs Arm B. No significant difference was seen in RECIST, PET or CA 19-9 between the arms. More patients in Arm B (45%, n = 5) than in Arm A (25%, n = 3) discontinued treatment early, mainly due to progression of disease, SAE or physician choice. Of all of the patients who completed 6 cycles of treatment, 78% of patients in Arm A, and 17% of patients in Arm B were deemed resectable; and 44% in Arm A vs 17% in Arm B underwent resection. The primary reasons in patients, who scored as eligible but resected were: metastatic disease, SAE, and physician decision. An improved resection rate was associated with a trend towards improved OS in Arm A.

Conclusions

Improved resection rate combined with increased median OS in Arm A suggests that pamrevlumab is a valuable addition to neoadjuvant therapy in LAPC patients without added toxicity, and that this combination therapy may have a positive impact on OS in LAPC patients.

Clinical trial identification

NCT01890265

Legal entity responsible for the study

Fibrogen Inc.

Funding

Fibrogen Inc.

Disclosure

E. Carrier: Consultant to Targazyme Full time employee of Fibrogen. V. Picozzi: Research funding from Celgene. K. Mody: Research Support: Ipsen, Senwha, Medimmune, Tracon. J. Winter: Research grant from American Cancer Society. J. Glaspy: Consultant for Fibrogen. Research grant from Fibrogen. K. Lipson, S. Porter, E. Kouchakji: Full time employee of Fibrogen. All other authors have declared no conflicts of interest.

Background

Muparfostat is an investigational new drug which deters tumor growth by blocking tumor angiogenesis and prevents tumor cells from spreading via heparanase inhibition. Previous phase II trial of muparfostat demonstrated good tolerability and favorable clinical response.

Methods

This international multicenter clinical trial was conducted in Asia-Pacific region (Taiwan, Korea, China, and Hong-Kong) from 2011. A total of 520 HV-HCC patients after surgical resection were randomized (1:1) to receive injection of either muparfostat (160 mg/day, 4-days-on/3-days-off, 3-weeks-on/1-week-off) or placebo for 52 weeks and followed up for 96 weeks. The primary endpoint was centrally assessed disease-free survival (DFS). Secondary endpoints included overall survival (OS), time to recurrence, and safety.

Results

Baseline patient demographics and characteristics were balanced between the treatment and placebo arms. All subjects completed the 52-week treatment. After interim analysis in 2014, the trial was concluded in 2015. The final intention-to-treat analysis (N = 519) yielded a non-significant result (p > 0.05) on DFS, not reaching the primary end point. Nevertheless, per-protocol analysis (N = 423) revealed a possible positive protective effect in subgroup patients with microvascular invasion. Muparfostat showed a significant prolongation in the disease-free time after completion of the 1-year treatment (hazard ratio: 0.13, 95% CI: 0.017 - 0.991, p = 0.049). Muparfostat had a good safety profile. There were five clinically suspected cases of heparin-induced thrombocytopenia but only one was confirmed.

Conclusions

Despite the DFS was not improved in the overall treatment group, muparfostat could significantly prolong the DFS in the microvascular-invasion subgroup, comprising 40% of the trial population. The finding potentiated muparfostat as single therapy or in combination with other anti-cancer agents for future HCC adjuvant therapy trials.

Clinical trial identification

PATRON/NCT01402908

Legal entity responsible for the study

Medigen Biotechnology Corporation

Funding

Medigen Biotechnology Corporation

Disclosure

P-J. Chen: Honorarium from Medigen Biotechnology Corporation. K-L. Lai: Employee of Medigen Biotechnology Corporation. All other authors have declared no conflicts of interest.

Background

REG improved overall survival (OS) and time to progression (TTP) versus placebo in pts with HCC who progressed during prior sorafenib in the phase 3 RESORCE trial. This exploratory analysis evaluated potential correlations between baseline plasma protein levels and REG clinical benefit (OS and TTP) in RESORCE.

Methods

Baseline plasma samples were available from 499/573 pts. A total of 266 circulating proteins valid for analysis were quantified by a Luminex assay (Myriad RBM). The predictive and prognostic effects (HR and 95% CI) were evaluated using a Cox proportional hazards model with protein levels measured as a continuous variable. The predictive effect was modeled as a protein–treatment interaction effect and subjected to Akaike information criterion (AIC)-based selection to assess its association with OS and TTP. Subgroup analysis was done on proteins identified as significant for OS and TTP to generate a patient-wise protein composite score.

Results

The overall and biomarker cohorts were similar for demographic variables and outcomes. Five proteins were predictive for OS (Table), but were not prognostic; 47 were predictive for TTP (6 were prognostic) and included the 5 proteins predictive for OS. In general, the REG treatment benefit for OS was maintained in dichotomized, quartile, and STEPP subgroup analyses, with lower protein levels correlating with improved treatment benefit. However, composite scores integrating information across predictive proteins indicated that in a small group of pts (n = 20 OS; n = 8 TTP) a high protein concentration was associated with a reduced treatment effect.Table:

625PD

Conclusions

Although this exploratory analysis suggests that most pts with HCC derive benefit from REG treatment, multiple proteins were identified as potentially predictive for OS and TTP treatment benefit with REG. Further analyses including biochemical and clinical factors are warranted.

Clinical trial identification

NCT01774344

Legal entity responsible for the study

Bayer

Funding

Bayer

Disclosure

M. Teufel: Employment & Stock Ownership: Bayer. K. Köchert: Employment: Bayer. G. Meinhardt: Employment and Stock Ownership: Bayer. R.S. Finn: Consulting and Advisory Role: Bayer, Pfizer, Novartis, BMS, Eisai. J.M. Llovet: Research/Education Grant: Bayer, Blueprint Medicines, BI, Incyte Advisory Board: Bayer, Eisai, BMS, Eli Lilly. Consulting: Eli Lilly, Bayer, BMS, Blueprint Medicines, Eisai, Celsion, BI. J. Bruix: Research/Education Grant: Daiichi Sankyo, ArQule, Bayer, Sirtex. Honoraria: Gilead, AbbVie, Kowa, Bayer, BTG, ArQule, Terumo, Sirtex, BMS, Eisai, BI, Novartis, OSI, Roche, Onxeo. Advisory Board: Bayer, Kowa, BTG, ArQule, Terumo, Sirtex, BMS, Eisai, Novartis, OSI, Roche, Onxeo. Consulting: Gilead, AbbVie, Kowa, Bayer, BTG, ArQule, Terumo, Sirtex, BMS, BI, Kowa, Novartis, OSI, Roche, Onxeo, Daiichi Sankyo, Abbot, Glaxo, Eli Lilly.

Background

Postoperative S-1 for 1 year (corresponding to 8 courses) is a standard adjuvant chemotherapy for p-stage II gastric cancer based on ACTS-GC phase III study comparing surgery alone and S-1. Duration of adjuvant chemotherapy for 1 year selected in ACTS-GC was not based on solid evidence while 6 months are established for colon cancer based on several phase III studies to compare duration. It remains unclear whether S-1 for 1 year could be shortened to 6 months (corresponding to 4 courses) without worsening the survival.

Methods

We conducted a multi-center phase III trial to confirm non-inferiority in relapse-free survival (RFS) of 4 courses S-1 to 8 courses S-1 in p-stage II gastric cancer. Key eligibility criteria were p-stage II except T1 and T3N0 (7^th edition of TNM), performance status 0-1, R0 resection with D2 lymph node dissection for ≥c-stage II or D1+ lymph node dissection for c-stage I, within 7 weeks after surgery, and age between 20 and 80 years. Primary endpoint was RFS and secondary endpoints included overall survival (OS), time to treatment failure (TTF), and adverse events. Patients were randomized into 4 course S-1 or 8 courses S-1. 80 mg/m² of S-1 was administered for 4 weeks with a rest for 2 weeks as one course. Total sample size was determined to be 1,000 with 3-year RFS of 85% in both arms and non-inferiority margin of hazard ratio (HR) of 1.37, one-sided alpha of 5% and 80% power.

Results

Between Feb 2012 and Mar 2017, 590 patients were enrolled in this study. Among them, 528 patients were analyzed at the first planned interim analysis at Mar 2017. JCOG Data and Safety Monitoring Committee recommended early termination of the trial because the point estimate of HR was greater than non-inferiority margin of HR, which met the prespecified criteria for early stopping. The study was closed on the basis of futility. RFS at 3 years was 88.9% for 4-courses arm and 95.3% for 8-courses arm (HR 2.52, 95% CI 1.11-5.77). OS at 3 years was 91.7% for 4-courses arm and 97.7% for the 8-courses arm (HR 5.18, 95% CI 1.50-17.89).

Conclusions

Postoperative S-1 adjuvant chemotherapy for p-stage II gastric cancer should be continued until 1 year so far as feasible.

Clinical trial identification

UMIN000007306, released on 16th Feb 2016

Legal entity responsible for the study

Japan Clinical Oncology Group (JCOG)

Funding

Japan Agency for Medical Research and Development and the National Cancer Center Research and Development Fund

Disclosure

T. Yoshikawa, N. Boku, M. Sasako: Lecture fee from Taiho, Eli Lilly, and Chugai Pharmaceutical. M. Terashima, H. Yabusaki, S. Ito, T. Sano: Lecture fee from Taiho. H. Fukuda: Lecture fee from Taiho Pharma, Chugai Pharmaceutical. All other authors have declared no conflicts of interest.

Background

To evaluate the prognostic significance of the eighth edition of American Joint Committee on Cancer (AJCC) TNM staging classification for gastric cancer.

Methods

Data from 4,957 consecutive patients who underwent radical gastrectomy between 1997 and 2014 were retrieved from our database. The prognostic value of the eighth edition was compared with that of the seventh edition of the AJCC TNM classification. The analysis was repeated in an external validation set.

Results

Significant differences in 5-year overall survival (OS) rates were observed for each TNM stage when using the eighth edition system, and smaller AIC values and a higher c-statistic were observed relative to those of the seventh edition. However, the OS rates in each subgroup of stage III patients in the eighth edition were significantly different. Additionally, patients with the same pN stage, namely the pT4a and pT4b groups, showed similar 5-year OS. Based on the survival data, we propose a simplified staging system. In the improved TNM (iTNM) staging system, the subgroups of a given TNM stage do not have statistically significant OS differences. The iTNM staging exhibits superior prognostic stratification, with lower AIC values and a higher c-statistic than the eighth edition TNM classification. Similar results were obtained with the external validation dataset.

Conclusions

The eighth edition of the AJCC TNM classification provides superior prognosis to that of the seventh edition. However, it remains associated with some stage migration. The iTNM staging system permits simplification and slightly better prognostic prediction.

Legal entity responsible for the study

Changming Huang

Funding

None

Disclosure

All authors have declared no conflicts of interest.