Dose-finding study of intensive weekly alternating schedule of docetaxel, 5-fluorouracil, and oxaliplatin, FD/FOx regimen, in metastatic gastric cancer

Introduction Proper administration timing, dose-intensity, efficacy/toxicity ratio of triplet docetaxel (DTX), 5-fluorouracil (5-FU), and oxaliplatin (OXP) should be improved to safely perform three-drugs intensive first line in advanced gastric cancer (GC). This dose-finding study investigated recommended 5-FU and OXP doses, safety of triplet regimen and preliminary activity. Methods Schedule: 12h-timed-flat-infusion 5-FU 700-1000 mg/m2/d 1-2, 8-9, 15-16, 22-23, with 100 mg/m2/d increase for dose level; DTX 50 mg/m2 d 1, 15 fixed dose, OXP at three increasing dose-levels 60-70-80 mg/m2 d 8, 22, every 4 weeks. Intra- and inter-patients dose-escalation was planned. Results Ten fit <75 years patients were enrolled: median age 59; young-elderly 4 (40%). From first to fifth dose level, 5 patients (1 per cohort) were enrolled according to intra-patient dose escalation, no dose-limiting toxicity (DLT) were reported. At sixth level, 1 DLT, G2 diarrhea, was reported, thus other 2 patients were enrolled, DLT 1/3 patients (33%). Maximum tolerated dose (MTD) was not reached. 5-FU and OXP recommended doses (RD) were 1000 mg/m2/d and 80 mg/m2, respectively. To confirm RD, other 3 patients were enrolled, without DLT. Cumulative G3-4 toxicities were: neutropenia 50%, leucopenia 20%, hypoalbuminemia 10%, mucositis 10%, asthenia 20%. Limiting toxicity syndromes were 30%, 25% in young-elderly, all multiple site. Objective response rate intent-to-treat 60%, disease control rate 90%. After 15 months follow-up, progression-free and overall survival, 6 and 17 months, respectively. Conclusions First line intensive FD/FOx regimen adding DXT/5-FU/OXP can be safely administered at recommended doses in advanced GC, with promising high activity and efficacy.


INTRODUCTION
Clinical management of advanced gastric cancer (GC) faces with different options of medical treatment strategies according to patients' fitness (age, performance status (PS), comorbidities), extension of primary tumor and related symptoms, influencing nutritional and functional conditions. Over the last 40 years, different active drugs were evaluated, and used in mono, doublet, and triplet chemotherapy combinations, improving activity, quality of life (QoL), and overall survival (OS). 5-fluorouracil (5FU)-based regimens consisting of mono, doublet or triplet combinations of chemotherapeutic drugs, improved activity and efficacy of first line advanced or metastatic GC. 5-FU, doxorubicin plus mitomycin (FAM) and 5-FU plus doxorubicin (Adriamycin) (FA) did not significantly increased OS vs 5-FU alone [1]. Epirubicin, cisplatin, and 5-FU (ECF) vs FAMTX significantly improved survival and QoL: overall response rate (ORR) 45 vs 21%, progression-free survival (PFS) 7.4 vs 3.4 months, OS 8.9 vs 5.7 months [2]. Mitomycin, cisplatin, and protracted venous-infusion (PVI) 5-FU, MCF regimen, compared with ECF, did not significantly increased outcomes: ORR 44.1 vs 42.4%, PFS 7 months for both regimens, OS 8.7 vs 9.4 months; QoL was better with ECF [3].
Major challenge of more drugs addition in a chemotherapy regimen is designing proper schedule and doses, providing the adequate balance between dose intensity (DI) of each drug and safety. DTX addiction to cisplatin/5-FU-based triplet chemotherapy regimen was evaluated in randomized studies [9,10], at different doses and schedules, with significantly increased toxicity, limiting the favourable impact and expected efficacy of the association. In phase II/III V325 trial, DCF significantly increased outcomes compared with CF [9]: ORR 37 vs 25%, P 0.01, PFS 5.6 vs 3.7 months, P < 0.001, and OS 9.2 vs 8.6 months, P 0.02.
We previously developed, in metastatic colorectal cancer setting, clinical trials proposing the concept of alternating chemotherapy administration schedules, as well as 12h-timed-flat-infusion (TFI)/5-FU administration modality, to optimize safety profile and maintain adequate dose intensity of each drug, in order to intensify first line regimens in fit patients [24][25][26][27][28][29]. The present dose-finding study, proposing intensive triplet chemotherapy combining first line DXT/OXP/5-FU in metastatic GC patients, assess OXP and 5-FU doses to be recommended in association with DXT for prospective clinical trials, safety and preliminary activity. www.oncotarget.com

Activity and efficacy
Overall, 10 patients were enrolled (Table 4), 7 treated in the dose escalation phase and 3 at the recommended doses. In the intent-to-treat and as-treated analyses all 10 patients were evaluable: ORR was 60% (α 0.05, CI ± 32). We observed 1 complete and 5 partial responses, 3 stable disease and 1 progression. Disease Control Rate (DCR) was 90% (α 0.05, CI ± 19). After a median follow-up of 15 months, median PFS was 6 months (3-15): 9 events occurred. Median OS was 17 months (5+ -26): 7 events occurred. Secondary resection of liver metastasis was performed in 1 patient with PFS of 10 months, and clinical complete response after triplet chemotherapy regimen.
Second line treatments were CPT-11 or ramucirumab-based chemotherapy associations in suitable patients.
Trastuzumab addiction to capecitabine/ cisplatin or 5-FU/cisplatin in HER2 positive patients significantly improved OS up to 16 vs 11.8 months in immunohistochemistry (IHC) 2+ and fluorescence in-situ hybridization (FISH) positive or IHC3+ [31]. Most common adverse events were: nausea (67 vs 63%), vomiting (50 vs 46%), neutropenia (53 vs 57%), cardiac adverse events (6% both arms). Definition of a feasible and safe triplet chemotherapy schedule could be potentially developed for a more intensive first line regimen adding trastuzumab in HER2 positive metastatic GC patients.
In metastatic GC patients, progressed after first-line platinum-or fluoropyrimidine-containing chemotherapy, OS was significantly increased to 5.2 vs 3.8 months P 0.047, with ramucirumab, 8 mg/kg every 2 weeks, compared with placebo [37]. Addiction of ramucirumab to paclitaxel, after first-line platinum plus fluoropyrimidine with or without anthracycline, significantly increased OS up to 9.6 vs. 7.4 months, P 0.017 [38]. The increasing efficacy of ramucirumab plus taxane as second line treatment point the discussion on the possibility to adopt a sequential treatment strategy alternative to a more intensive first line regimen in metastatic GC, particularly in patients unfit for such an intensive combined therapy, due to clinical parameters, age, comorbidity, functional/ nutritional conditions.

Patient eligibility
Patients were eligible if they had histologically confirmed diagnosis of measurable metastatic GC; age 18-75 years; World Health Organization (WHO) PS ≤ 2;  [30]. Primary CIRS stage consisted of: independent Instrumental Activity of Daily Living (IADL), and absent or mild grade comorbidities; intermediate CIRS stage consisted of dependent or independent IADL, and < 3 mild or moderate grade comorbidities. Patients with secondary CIRS stage, consisting of ≥ 3 comorbidities or a severe comorbidity, with or without dependent IADL, were not enrolled. Criteria to define patients unfit for the proposed treatment strategy were: uncontrolled severe diseases; cardiovascular disease (uncontrolled hypertension, uncontrolled arrhythmia, ischemic cardiac diseases in the last year); thromboembolic disease, coagulopathy, preexisting bleeding diatheses.
First line DTX association to 5-FU and OXP, was proposed to consecutive eligible metastatic GC patients as a treatment strategy in clinical practice, chosen among those in indication and approved by Agenzia Italiana del Farmaco (AIFA) for administration in label in Italian public hospitals, and published in Gazzetta Ufficiale Repubblica Italiana ("Elenco dei Medicinali erogabili a totale carico del Servizio Sanitario Nazionale", Gazzetta Ufficiale Repubblica Italiana N.1, 2 Gennaio 2009). Thus, it was not necessary any approval by ethics committee and institutional review board, because patients were treated with conventional treatments without any additional medical intervention out of the best common clinical practice. All patients provided written, informed consent to the proposed in label treatment strategy. Treatment was conducted in accordance with the Declaration of Helsinki.

Study design
Physical examination and routine laboratory tests were performed at baseline and every week on-treatment, including complete blood cell count, electrolytes, liver and renal function, urine examination and coagulation function; tumor markers every 4 weeks; electrocardiogram every cycle and echocardiogram at baseline, and every 3 cycles of treatment.
Primary end-point was to define the recommended 5-FU and OXP doses. Secondary end-points were evaluation of toxicity, ORR, PFS, OS. Toxicity was registered every week according to National Cancer Institute Common Toxicity Criteria (version 3.0). DLT was defined: in the intra-patient step, as G2 non-haematological or G3 haematological toxicity; in the inter-patient step, as grade 3-4 non-haematological toxicity (mainly represented by diarrhea, mucositis, neurotoxicity, hand-foot syndrome, asthenia), grade 4 hematologic toxicity (neutropenia), febrile neutropenia, grade 3-4 thrombocytopenia, or any toxicity determining > 2 weeks treatment delay.
To discriminate individual safety, LTS, consisting of at least a limiting toxicity (LT) associated or not to other limiting or G2 toxicities, were evaluated, as previously reported [25,28]. LTS were classified as LTS single site (LTS-ss), characterized only by the LT, and LTS multiple sites (LTS-ms), ≥ 2 LTs or a LT associated to other, at least G2, non-limiting toxicities.
ORR was evaluated according to RECIST criteria [39]; pathologic complete response was defined as absence of residual cancer cells in surgically resected specimens; PFS and OS, using Kaplan-Meier method [40]. PFS was defined as length of time between the beginning of treatment and disease progression or death (resulting from any cause) or to last contact; OS as length of time between the beginning of treatment and death or to last contact.
Patients were evaluated at baseline and after treatment by a multidisciplinary team, consisting of medical oncologist, radiotherapist, surgeon, and radiologist, to dynamically evaluate multimodality treatment strategy. Surgical resection was defined R0, if radical surgery, R1, if microscopic residual cancer cells were present at resection margins. Surgery was recommended > 4-6 weeks after chemotherapy discontinuation.
Clinical evaluation of response was planned by CTscan; PET and MRI were added based on investigators' assessment; response on primary gastric tumor was also evaluated by endoscopy. Follow-up was scheduled every three months up to disease progression or death.

Statistical design
This dose-finding study was developed to verify recommended OXP dose, by 3 escalating dose steps at 60, 70 and 80 mg/m 2 , and 5-FU dose, by 4 escalating dose steps at 700, 800, 900 and 1000 mg/m 2 /d, according to an intra-and inter-patient approach [41,42]. It is preliminary to a phase II study, evaluating activity and efficacy of triplet chemotherapy association, assuming as minimal interesting activity a rate of 40%, according to Simon two stage design [42].

CONCLUSIONS
The present dose-finding study proposed a feasible and safe schedule of triplet DTX/5-FU/OXP association, FD/FOx regimen, at 5-FU and OXP recommended doses 1000 mg/m 2 /d and 80 mg/m 2 , respectively, that should be evaluated in prospective trials as first line treatment in metastatic GC patients.

Author contributions
GB contributed to the conception and design of the study, in the provision of study materials of patients, in the clinical management, in the data analysis and interpretation, in the manuscript writing. ER contributed to the conception and design of the study, in clinical management, in the data analysis and interpretation, in the manuscript writing. SM, EC contributed in schedule designing. AG, AR contributed in the data interpretation. ADM, GC provided biological analysis. SG provided surgical evaluations. All authors participated in the collection and/or assembly of data. All authors read, revised and approved the final manuscript.

CONFLICTS OF INTEREST
Authors declare that they have no conflicts of interest.

FUNDING
None.