A randomised phase II trial of two sequential schedules of docetaxel and cisplatin followed by gemcitabine in patients with advanced non-small-cell lung cancer

Purpose

The aim of this study was to determine the activity and toxicity of two sequential chemotherapy regimens in the first-line treatment of advanced non-small-cell lung cancer (NSCLC).

Methods

Eighty-eight chemonaive patients with stage IIIB/IV NSCLC were randomised to receive either three cycles of 75?mg/m² cisplatin plus 75?mg/m² docetaxel, both administered on day 1 every 21?days, followed by three cycles of 1,200?mg/m² gemcitabine on days 1 and 8 every 3?weeks (arm A), or three cycles of 25?mg/m² cisplatin plus 25?mg/m² docetaxel on days 1, 8 and 15 every 28?days, followed by three cycles of 1,200?mg/m² gemcitabine on days 1 and 8 every 3?weeks (arm B).

Results

Of the evaluable patients, 61% in arm A (n?=?41) and 36% (n?=?44) in arm B completed treatment as per the protocol. The best tumour response rates were as follows (arm A and arm B): complete response: 2.4 and 2.3%; partial response: 39 and 20.4%; stable disease: 26.8 and 13.6%; and progressive disease: 31.8 and 45.4%. The median progression-free and overall survival were 3.9 and 12.3?months in arm A, respectively, 3.1 and 7.7?months in arm B. Grade 3?C4 adverse events were more common in arm A. Grade 3?C4 neutropenia was the main toxicity observed (56.1% in arm A and 11.4% in arm B).

Conclusions

Our data demonstrate the feasibility of a sequential approach of cisplatin plus docetaxel followed by single-agent gemcitabine. Weekly administration of platinum-docetaxel is associated with an improved safety profile but lower efficacy than the conventional three-weekly schedule (registration ID 2004-001044-72).     

A Phase II Study of Capecitabine, Oxaliplatin, and Cetuximab with or Without Bevacizumab as Frontline Therapy for Metastatic Colorectal Cancer. A Fox Chase Extramural Research Study

Objectives

Dual inhibition of vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) demonstrated initial promise in clinical trials. This phase II study tested the efficacy and safety of capecitabine, oxaliplatin, and cetuximab with or without bevacizumab as first-line treatment for metastatic colorectal cancer patients.

Methods

Patients were randomized to receive capecitabine 850 mg/m² PO twice daily for 14 days, oxaliplatin 130 mg/m² IV day 1, and cetuximab 400 mg/m² IV loading dose followed by 250 mg/m² IV days 1, 8, and 15 with (Arm A) or without (Arm B) bevacizumab 7.5 mg/kg IV day 1 every 21 days. Tumor samples were collected and retrospectively analyzed for KRAS mutation status. The primary endpoint was response rate, with time to progression (TTP) and overall survival (OS) as secondary objectives.

Results

Twenty-three patients (12 in Arm A, 11 in Arm B) were enrolled onto the study. Median follow-up was 25.9 months. Both treatments were well tolerated, with expected higher rates of grade 1/2 hypertension and bleeding in Arm A. The overall response rate was 54% (36.4% in Arm A and 72.7% in Arm B). Median time to progression was 8.7 months in Arm A and 14.4 months in Arm B. The median survival was 18.0 months in Arm A and 42.5 months in Arm B. The study was prematurely terminated after other studies reported inferior outcomes with dual antibody therapy.

Conclusions

Although terminated early, the study supports the detrimental effect of combining VEGF and EGFR inhibition in metastatic colorectal cancer.     

A Phase I study to assess the safety, tolerability, and pharmacokinetics of AZD4877, an intravenous Eg5 inhibitor in patients with advanced solid tumors

Purpose

Inhibition of kinesin spindle protein or Eg5 causes the formation of monoastral mitotic spindles, which leads to cell death. AZD4877 is a specific, potent inhibitor of Eg5.

Methods

This was a Phase I, open-label, two-part study to evaluate the maximum tolerated dose (MTD) and safety and tolerability of AZD4877 in patients with advanced solid malignancies. In part A, the MTD of AZD4877, administered as three weekly 1-h intravenous (iv) infusions in a 28-day schedule, was determined by evaluating dose-limiting toxicity (DLT). In part B, the safety, tolerability, and pharmacokinetic profile of AZD4877 at the MTD were evaluated.

Results

In part A, 29 patients received at least one dose of AZD4877 (5?mg, n?=?4; 7.5?mg, n?=?4; 10?mg, n?=?3; 15?mg, n?=?3; 20?mg, n?=?3; 30?mg, n?=?6; 36?mg, n?=?3; 45?mg, n?=?3). The MTD was defined as 30?mg, with the primary DLT being neutropenia. Although exposures appeared to be similar at the AZD4877 20 and 30?mg doses, dose reductions and omissions were higher in the 30-mg cohort; therefore, an intermediate dose, 25?mg, was evaluated in part B (n?=?14). In part B, neutropenia remained the most commonly reported causally related adverse event. Exposure to AZD4877 was approximately dose proportional. Severity of neutropenia was related to exposure.

Conclusion

The MTD of AZD4877 given as a 1-h iv infusion on days 1, 8, and 15 of a 28-day cycle was 30?mg. At the selected 25?mg dose, AZD4877 had an acceptable safety profile.     

A multicenter phase II trial of docetaxel and capecitabine as salvage treatment in anthracycline- and taxane-pretreated patients with metastatic breast cancer

Objective

To evaluate the efficacy and safety of docetaxel plus capecitabine (DC) combination as salvage treatment in anthracycline- and taxane-pretreated patients with metastatic breast cancer (MBC).

Patients and treatment

Patients with MBC who had disease progression after initial chemotherapy with anthracyclines (n?=?29; 100?%) and taxanes (n?=?11; 37.9?%) were treated with oral capecitabine 950?mg/m² twice daily on days 1?C14 and docetaxel 75?mg/m² on day 1 every 3?weeks. Nineteen (65.5?%) patients received this regimen as second line and 10 (34.5?%) as???3rd line of therapy. All patients were evaluable for response and toxicity.

Results

Complete response occurred in two (6.9?%) patients and partial response in eleven (37.9?%) for an overall response rate of 44.8?% (95?% CI 26.7?C62.9?%). Eleven women (37.9?%) had stable disease and five (17.2?%) progressive disease. Of the eleven patients previously treated with anthracyclines and taxanes, five (45.5?%) responded to DC combination. The median duration of response was 5.7?months (range 3.4?C64.2), the median time to disease progression 9.3?months (range 1.2?C58), and the median overall survival 25.5?months. No toxic death occurred. Neutropenia grade 4 occurred in 58.6?% of patients and three of them (10.3?%) developed neutropenic fever. Non-hematological toxicities were manageable with grade 3 hand-foot syndrome occurring in 6.9?% of the patients, fatigue in 3.4?%, and neurotoxicity in 3.4?%.

Conclusion

The DC combination is a valuable regimen as salvage treatment in anthracycline- or anthracycline and taxane-pretreated patients with MBC.     

A phase I and pharmacokinetic study of elisidepsin (PM02734) in patients with advanced solid tumors

Purpose

To determine the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), and recommended phase II dose (RD) of elisidepsin.

Methods

Eligible patients with refractory, advanced solid tumors received elisidepsin as 24-h intravenous infusion every 3?weeks. Pharmacokinetic profiles were analyzed during cycles 1 and 2.

Results

Forty-two patients received elisidepsin at doses from 0.5 to 6.8?mg/m². The MTD was 6.8?mg/m², and the RD was 5.5?mg/m². Cohort expansion at the RD was done at a fixed dose (FD) of 10?mg, considered equivalent to 5.5?mg/m². DLTs (reversible grade 3 transaminase increases) occurred at 6.8?mg/m² (n?=?2 patients), 5.5?mg/m² (n?=?1), and 10?mg FD (n?=?1). One patient with esophageal adenocarcinoma achieved complete response for >38?months, and 12 patients had disease stabilization (8 for ≥3?months). Median time-to-progression for these 12 patients was 4.8?months. Plasma elisidepsin concentrations increased with dose. No drug accumulation between cycles was found. No correlation was observed between body surface area (BSA) and plasma clearance; therefore, elisidepsin was given as flat dose (in mg) in the expansion cohort at the RD and in ongoing clinical trials.

Conclusions

Elisidepsin is well tolerated with predictable reversible transaminase increases. Encouraging preliminary evidence of antitumor activity was observed.     

A two-part Phase II study of cediranib in patients with advanced solid tumours: the effect of food on single-dose pharmacokinetics and an evaluation of safety, efficacy and imaging pharmacodynamics

Background

Cediranib (RECENTIN?) is an oral, highly potent VEGF inhibitor. This study evaluated the effect of food on the pharmacokinetics of cediranib and compared the administration of continual cediranib via two dosing strategies using this as a platform to investigate pharmacodynamic imaging biomarkers.

Methods

Sixty patients were randomised to receive two single doses of cediranib in either fed/fasted or fasted/fed state (Part A). In continual dosage phase (Part B), patients were randomised to a fixed-dose or dose-escalation arm. Exploratory pharmacodynamic assessments were performed using DCE-MRI and CT enhancing fraction (EnF).

Results

In part A, plasma AUC and C _max of cediranib were lower in the presence of food by a mean of 24 and 33%, respectively (94% CI: AUC, 12?C34% and C _max, 20?C43%), indicating food reduces cediranib plasma exposure. In part B, cediranib 30?mg/day appeared to be the most sustainable for chronic dosing. Continuous cediranib therapy was associated with sustained antivascular effects up to 16?weeks, with significant reductions in DCE-MRI parameters and CT EnF.

Conclusions

It is recommended that cediranib be administered at least 1?h before or 2?h after food. Evidence of antitumour activity was observed, with significant sustained effects upon imaging vascular parameters.     

Cisplatin-induced emesis: systematic review and meta-analysis of the ferret model and the effects of 5-HT3 receptor antagonists

Purpose

The ferret cisplatin emesis model has been used for ~30?years and enabled identification of clinically used anti-emetics. We provide an objective assessment of this model including efficacy of 5-HT₃ receptor antagonists to assess its translational validity.

Methods

A systematic review identified available evidence and was used to perform meta-analyses.

Results

Of 182 potentially relevant publications, 115 reported cisplatin-induced emesis in ferrets and 68 were included in the analysis. The majority (n?=?53) used a 10?mg?kg^?1 dose to induce acute emesis, which peaked after 2?h. More recent studies (n?=?11) also used 5?mg?kg^?1, which induced a biphasic response peaking at 12?h and 48?h. Overall, 5-HT₃ receptor antagonists reduced cisplatin (5?mg?kg^?1) emesis by 68% (45?C91%) during the acute phase (day 1) and by 67% (48?C86%) and 53% (38?C68%, all P?<?0.001), during the delayed phase (days 2, 3). In an analysis focused on the acute phase, the efficacy of ondansetron was dependent on the dosage and observation period but not on the dose of cisplatin.

Conclusion

Our analysis enabled novel findings to be extracted from the literature including factors which may impact on the applicability of preclinical results to humans. It reveals that the efficacy of ondansetron is similar against low and high doses of cisplatin. Additionally, we showed that 5-HT₃ receptor antagonists have a similar efficacy during acute and delayed emesis, which provides a novel insight into the pharmacology of delayed emesis in the ferret.     

Phase II study of use of a single cycle of induction chemotherapy and concurrent chemoradiotherapy containing capecitabine/cisplatin followed by surgery for patients with resectable esophageal squamous cell carcinoma: long-term follow-up data

Purpose

This phase II study evaluated the feasibility and efficacy of one cycle of induction chemotherapy, followed by concurrent chemoradiotherapy (CRT) featuring capecitabine/cisplatin, followed in turn by surgery, in the treatment of patients with resectable esophageal squamous cell carcinoma.

Methods

Between March 2003 and April 2005, 54 patients with stage II or III esophageal cancer were treated with induction chemotherapy (cisplatin 60?mg/m² on day 1; capecitabine 1,000?mg/m² bid on days 1?C14) followed by concurrent radiotherapy (46?Gy in 23 fractions) and chemotherapy (cisplatin 30?mg/m² on days 1, 8, 15, and 22; capecitabine 800?mg/m² bid 5?days/week). Surgery was performed within 8?weeks of the end of radiotherapy.

Results

Median age of the patients was 64.5?years (range, 45?C74?years). After CRT, 52 patients (96%) showed a clinical response, including 26 (48%) who exhibited a complete response (CR). Surgery was performed on 41 patients (76%), with 20 (37%) achieving pathologic CR and 3 (6%) dying of postoperative pneumonia. At a median follow-up time of 74.2?months (range, 64.3?C84.8?months), 16 patients (30%) had experienced tumor recurrence and 36 (67%) had died. Of the 41 patients who underwent esophagectomy, 5 (12%) had exclusively locoregional disease and 7 (17%) had distant metastasis, whereas no one had both. The 5-year progression-free and overall survival rates were 30.2% (95% confidence interval [CI], 18.0?C42.4%) and 37.0% (95% CI, 24.1?C50.0%), respectively.

Conclusions

A trimodal approach, consisting of a single cycle of induction chemotherapy, CRT containing capecitabine and cisplatin, and surgery, was feasible and effective in patients with resectable esophageal squamous cell carcinoma.     

Pharmacokinetics of eribulin mesylate in patients with solid tumors and hepatic impairment

Purpose

The aim of this study was to determine the plasma pharmacokinetics of eribulin mesylate in patients with solid tumors with mild and moderate hepatic impairment.

Patients and methods

A phase I, pharmacokinetic study was performed in patients with advanced solid tumors and normal hepatic function or Child-Pugh A (mild) or Child-Pugh B (moderate) hepatic impairment. Treatments were given on day 1 and 8 of a 21-day cycle and consisted of 1.4, 1.1 and 0.7?mg/m² eribulin mesylate, for normal hepatic function, Child-Pugh A and B hepatic impairment, respectively. Also safety and anti-tumor activity were determined.

Results

Hepatic impairment increased exposure to eribulin. In patients with Child-Pugh A (N?=?7) and Child-Pugh B (N?=?5), mean dose-normalized AUC_0?C?? was 1.75-fold (90?% confidence intervals (CI): 1.16?C2.65) and 2.48-fold (90?% CI: 1.57?C3.92) increased, respectively, compared with patients who have normal function (N?=?6). The most frequently reported treatment-related events were alopecia (12/18) and fatigue (7/18) and these were observed across all groups. Nine patients (50?%) had stable disease as best response.

Conclusions

A reduced dose of 1.1 and 0.7?mg/m² of eribulin mesylate is recommended for patients with Child-Pugh A or B hepatic impairment, respectively.     

A phase IIa dose-finding and safety study of first-line pertuzumab in combination with trastuzumab,capecitabine and cisplatin in patients with HER2-positive advanced gastric cancer

Background:

Pertuzumab plus trastuzumab provides a more comprehensive blockade of HER2 signalling than trastuzumab alone. Therefore, we conducted a phase IIa study of the pharmacokinetics and safety of pertuzumab plus trastuzumab and chemotherapy in advanced gastric cancer (aGC).

Methods:

Patients received pertuzumab 840 mg for cycle 1 and 420 mg q3w for cycles 2–6 (Arm A) or pertuzumab 840 mg q3w for six cycles (Arm B). Trastuzumab, cisplatin and capecitabine were also given for six cycles, then trastuzumab q3w until disease progression or unmanageable toxicity. The co-primary endpoints were day 43 pertuzumab serum trough concentration (C_min) and safety.

Results:

Thirty patients were randomised. Mean pertuzumab C_min at day 43 was 40.0 μg ml⁻¹ (s.d.: 17.3) in Arm A and 62.7 μg ml⁻¹ (29.1) in Arm B. Mean day 43 C_min in Arm A was ∼37% lower than that seen in metastatic breast cancer. The safety profiles were similar between arms and treatment was well tolerated. Partial responses were achieved by 86% and 55% of patients in Arms A and B, respectively.

Conclusions:

On the basis of the pharmacokinetic and safety data, the 840 mg q3w pertuzumab dose has been selected for a phase III study of pertuzumab, trastuzumab and chemotherapy in HER2-positive aGC.     

Cediranib with mFOLFOX6 vs bevacizumab with mFOLFOX6 in previously treated metastatic colorectal cancer

Background:

Cediranib is a highly potent inhibitor of vascular endothelial growth factor (VEGF) signalling with activity against all three VEGF receptors. Bevacizumab is an anti-VEGF-A monoclonal antibody with clinical benefit in previously treated metastatic colorectal cancer (mCRC).

Methods:

Patients with mCRC who had progressed following first-line therapy were randomised 1 : 1 : 1 to modified (m)FOLFOX6 plus cediranib (20 or 30 mg day⁻¹) or bevacizumab (10 mg kg⁻¹ every 2 weeks). The primary objective was to compare progression-free survival (PFS) between treatment arms.

Results:

A total of 210 patients were included in the intent-to-treat (ITT) analysis (cediranib 20 mg, n=71; cediranib 30 mg, n=73; bevacizumab, n=66). Median PFS in the cediranib 20 mg, cediranib 30 mg and bevacizumab groups was 5.8, 7.2 and 7.8 months, respectively. There were no statistically significant differences between treatment arms for PFS (cediranib 20 mg vs bevacizumab: HR=1.28 (95% CI, 0.85–1.95; P=0.29); cediranib 30 mg vs bevacizumab: HR=1.17 (95% CI, 0.77–1.76; P=0.79)) or overall survival (OS). Grade ⩾3 adverse events were more common with cediranib 30 mg (91.8%) vs cediranib 20 mg (81.4%) or bevacizumab (84.8%).

Conclusion:

There were no statistically significant differences between treatment arms for PFS or OS. When combined with mFOLFOX6, the 20 mg day⁻¹ dose of cediranib was better tolerated than the 30 mg day⁻¹ dose.     

A Phase Ib study evaluating MNRP1685A,a fully human anti-NRP1 monoclonal antibody,in combination with bevacizumab and paclitaxel in patients with advanced solid tumors

Purpose

MNRP1685A is a human monoclonal antibody that blocks binding of vascular endothelial growth factor (VEGF), VEGF-B, and placental growth factor 2 to neuropilin-1 resulting in vessel immaturity and VEGF dependency. The safety of combining MNRP1685A with bevacizumab, with or without paclitaxel, was examined.

Methods

Patients with advanced solid tumors received escalating doses of MNRP1685A (7.5, 15, 24, and 36 mg/kg) with bevacizumab 15 mg/kg every 3 weeks in Arm A (n = 14). Arm B (n = 10) dosing consisted of MNRP1685A (12 and 16 mg/kg) with bevacizumab 10 mg/kg (every 2 weeks) and paclitaxel 90 mg/m² (weekly, 3 of 4 weeks). Objectives were to determine safety, pharmacokinetics, pharmacodynamics, and the maximum tolerated dose of MNRP1685A.

Results

Infusion reactions (88 %) and transient thrombocytopenia (67 %) represent the most frequent study drug-related adverse events (AEs). Drug-related Grade 2 or 3 proteinuria occurred in 13 patients (54 %). Additional study drug-related AEs occurring in >20 % of patients included neutropenia, alopecia, dysphonia, fatigue, and nausea. Neutropenia occurred only in Arm B. Grade ≥3 study drug-related AEs in ≥3 patients included neutropenia (Arm B), proteinuria, and thrombocytopenia. Two confirmed and three unconfirmed partial responses were observed.

Conclusions

The safety profiles were consistent with the single-agent profiles of all study drugs. However, a higher than expected rate of clinically significant proteinuria was observed that does not support further testing of MNRP1685A in combination with bevacizumab.     

Efficacy of trastuzumab in Japanese patients with HER2-positive advanced gastric or gastroesophageal junction cancer: a subgroup analysis of the Trastuzumab for Gastric Cancer (ToGA) study

Background

The Trastuzumab for Gastric Cancer (ToGA) study is the first international trial to include Japanese patients with human epidermal growth factor 2 (HER2) positive advanced/metastatic gastric or gastroesophageal junction cancer. ToGA showed that trastuzumab plus chemotherapy (capecitabine/cisplatin or 5-fluorouracil/cisplatin) improved overall survival in the overall population (hazard ratio 0.74). Regional differences in outcome in favor of Japanese populations were observed in other studies; therefore, subgroup analyses of ToGA may contribute to the evaluation of the potential benefits of this regimen in Japanese patients.

Methods

We performed subgroup analyses on 101 Japanese patients enrolled into ToGA (trastuzumab plus chemotherapy, n?=?51; chemotherapy, n?=?50).

Results

Median overall survival in the Japanese subgroup was 15.9?months (95% confidence interval 12–25) for trastuzumab plus chemotherapy and 17.7?months (95% confidence interval 12–24) for chemotherapy (hazard ratio 1.00; 95% confidence interval 0.59–1.69). After adjusting for prespecified covariates, the estimated hazard ratio for overall survival was 0.68 (95% confidence interval 0.36–1.27). Further post hoc and exploratory examinations supported the robustness of the adjusted hazard ratios.

Conclusions

After adjusting for imbalanced patient backgrounds between arms, overall survival of Japanese patients with human epidermal growth factor 2 positive advanced/metastatic gastric or gastroesophageal junction cancer who received trastuzumab plus chemotherapy was improved compared with patients who received chemotherapy alone.     

A phase I study of sunitinib combined with modified FOLFOX6 in patients with advanced solid tumors

Purpose

This phase I study assessed the safety, tolerability, maximum tolerated dose (MTD), pharmacokinetics, and preliminary antitumor effects of sunitinib combined with modified FOLFOX6 (mFOLFOX6).

Methods

Patients with advanced solid malignancies received mFOLFOX6 in 2-week cycles with escalating sunitinib doses (25, 37.5, and 50?mg/day) on three schedules: 2?weeks on, 2?weeks off (2/2); 4?weeks on, 2?weeks off (4/2); or continuous daily dosing (CDD). Patients received up to 8 treatment cycles (Schedule 2/2 and CDD schedule) or 6 cycles (Schedule 4/2). An expansion cohort enrolled patients with metastatic colorectal cancer at the Schedule 2/2 MTD.

Results

Overall, 53 patients were enrolled, with 43 evaluable for dose-limiting toxicity (DLT). On Schedule 2/2 (n?=?18), DLTs occurred in three patients at 50?mg/day (grade 4 neutropenia [n?=?1]; grades 3 and 4 thrombocytopenia [n?=?2]) and two patients achieved partial responses (PRs). On Schedule 4/2 (n?=?13), 37.5?mg/day exceeded the MTD with two DLTs (febrile neutropenia and grade 4 hypokalemia, respectively). On the CDD schedule (n?=?12), the MTD was 25?mg/day; one DLT (grade 3 stomatitis) was reported and two patients achieved PRs. The most common adverse events were neutropenia, fatigue, and thrombocytopenia. No clinically significant drug?Cdrug interactions were apparent between sunitinib, its metabolite SU12662, and mFOLFOX6.

Conclusions

Sunitinib combined with mFOLFOX6 had acceptable tolerability. The MTDs were sunitinib 50?mg/day on Schedule 2/2 and 25?mg/day on the CDD schedule. A MTD for Schedule 4/2 was not established.     

Phase I pharmacokinetic study of chronomodulated dose-intensified combination of capecitabine and oxaliplatin (XELOX) in metastatic colorectal cancer

Purpose

To evaluate the maximum tolerated dose (MTD) and pharmacokinetic profile of a chronomodulated, dose-intensified regimen of capecitabine in combination with oxaliplatin (XELOX) in metastatic colorectal cancer (mCRC).

Methods

Patients (N?=?18) with 0 or 1 line of prior chemotherapy received oxaliplatin 100?mg/m² on day 1 from 1400 to 1800 hours with escalating dose levels of capecitabine (2,500, 3,000, 3,500, 4,000, 4,500, and 5,000?mg) once daily taken at 2400 hours on days 1?C5. Each cycle lasted 14?days.

Results

The MTD of capecitabine was 4,500?mg. Transaminitis and anemia were the commonest non-hematologic and hematologic toxicities, respectively. Toxicities were generally mild, with only five occurrences of grade 3 toxicity and none of grade 4. There were no dose-limiting toxicities, defined as specific grade 3 or 4 toxicities occurring in the first two cycles of treatment. The objective response rate was 33.3?%, and median overall survival was 16.3?months (95?% CI: 11.2?C18.2?months). The maximum plasma concentration (C _max) and area under plasma concentration?Ctime curve from time 0 to infinity (AUC_[0?C??]) of the capecitabine metabolites in our fixed-dosing chronomodulated regimen were comparable to values seen with comparably dose-intense regimens but associated with significantly reduced toxicity.

Conclusions

Chronomodulated dose-intensified XELOX facilitates delivery of dose-intense treatment in mCRC with a favorable therapeutic index that is promising.     

Combination chemotherapy with S-1 plus cisplatin for gastric cancer that recurs after adjuvant chemotherapy with S-1: multi-institutional retrospective analysis

Background

It is unclear whether S-1 plus cisplatin is effective for patients with recurrent gastric cancer after adjuvant S-1 chemotherapy.

Methods

We retrospectively evaluated the efficacy of S-1 plus cisplatin in patients whose gastric cancer recurred after adjuvant S-1 chemotherapy.

Results

In the 52 patients evaluated, the median duration of adjuvant S-1 chemotherapy was 8.1?months, and the median recurrence-free interval (RFI) since the last administration of adjuvant S-1 was 6.4?months. Among the 36 patients with measurable lesions, 7 achieved a complete or partial response, and 13 were evaluated as having stable disease, for an overall response rate of 19.4% and a disease control rate of 55.6%. For all patients, the median progression-free survival (PFS) was 4.8?months, and the median overall survival (OS) was 12.2?months. Compared with patients with an RFI of <6?months (n?=?25), patients with an RFI of ≥6?months (n?=?27) had a significantly higher response rate (5.0 vs. 37.5%, respectively), longer PFS (2.3 vs. 6.2?months, respectively), and longer overall survival (7.3 vs. 16.6?months, respectively). According to a multivariate Cox model including performance status (PS) and reason for discontinuation of adjuvant S-1, an RFI of 6?months was still significantly associated with PFS and OS.

Conclusions

S-1 plus cisplatin is effective for patients with gastric cancer that recurs after adjuvant S-1 chemotherapy, especially for those with an RFI of ≥6?months.     

Use of low-dose combined therapy with gemcitabine and paclitaxel for advanced urothelial cancer patients with resistance to cisplatin-containing therapy: a retrospective analysis

Purpose

The prognosis of patients with advanced and recurrent urothelial cancer (UC) is poor. Although cisplatin (CDDP)-containing chemotherapy is the most effective regimen in these patients, there is no other established chemotherapeutic regimen. We administered combination therapy with low-dose gemcitabine (GEM) and paclitaxel (PTX), named low-dose gemcitabine?Cpaclitaxel (LD-GP) therapy, as salvage therapy for these patients. The aim was to evaluate the anti-tumoral effects, relief of pain, and toxicity of LD-GP therapy in patients with resistance to CDDP-containing therapy.

Patients and methods

Thirty-five patients with advanced UC, previously treated with CDDP-containing regimens, were treated with LD-GP therapy (GEM, 700?mg/m²?+?PTX, 70?mg/m² on day 1 and 8, repeated every 28?days). Pain was measured on a visual analog scale before and after treatment. Pain relief and survival were compared between this and other treatment regimens.

Results

None of the patients had complete response to LD-GP therapy. Partial response and stable disease were seen in 25.7 and 62.9?% of patients, respectively. Kaplan?CMeier curves showed better survival in patients with LD-GP therapy than with others (p?=?0.034). Twenty-eight patients (80.0?%) had adequate pain relief, and only two patients needed to increase their analgesics. Other regimens demonstrated pain relief in 30.4?% of patients. Common toxicities included leukopenia, with five patients requiring granular colony-stimulating factor therapy (14.3?%). The most common non-hematologic toxicity was fatigue (n?=?7, 17.1?%).

Conclusions

LD-GP therapy is feasible and well tolerated as salvage therapy in patients with advanced UC with resistance to CDDP-containing therapy.     

Concurrent use of capecitabine with radiation therapy and survival in breast cancer (BC) after neoadjuvant chemotherapy

Purpose

Capecitabine has been studied as a radiosensitizer, and our study seeks to examine the association of concurrent capecitabine/radiation therapy (RT) on event-free- (EFS) and overall survival (OS) in women with breast cancer (BC) with residual disease after neoadjuvant chemotherapy (NAC).

Methods/patients

In a retrospective study of women with BC who received adriamycin/taxane-based NAC from 2004–2016, we identified 21 women administered concurrent capecitabine/RT. To assess differences in survival, we selected a clinical control cohort (n?=?57) based on criteria used to select patients for capecitabine/RT. We also created a matched cohort (2:1), matching on tumor subtype, pathological stage and age (<?50 or 50+ years). Differences in EFS, using STEEP criteria, and OS, using all-cause mortality, between those who received capecitabine/RT and controls were assessed.

Results

Of the 21 women who received capecitabine/RT, median age was 52 years. The majority were pathologic stage III (n?=?15) and hormone receptor-positive/HER2-negative BC (n?=?20). In those receiving capecitabine/RT, there were 9 events, compared with 14 events in clinical and 10 events in matched controls. Capecitabine/RT was associated with worse OS in clinical (HR 3.83 95% CI 1.12–13.11, p?=?0.03) and matched controls (HR 3.71 95% CI 1.04–13.18, p?=?0.04), after adjusting for clinical size, pathological stage and lymphovascular invasion. Capecitabine/RT was also associated with a trend towards worse EFS in clinical (HR 2.41 95% CI 0.86–6.74, p?=?0.09) and matched controls (HR 2.68 95% CI 0.91–7.90, p?=?0.07) after adjustment.

Conclusion

Concurrent capecitabine/RT after NAC is associated with worse survival and should be carefully considered in BC.

     

Phase I clinical trial of hepatic arterial infusion of cisplatin in combination with intravenous liposomal doxorubicin in patients with advanced cancer and dominant liver involvement

Purpose

We conducted a phase I study of hepatic arterial infusion (HAI) cisplatin and systemic chemotherapy in patients with advanced cancer and dominant liver involvement.

Methods

Patients were treated with HAI cisplatin 100–125 mg/m² (and 3,000 IU heparin) intraarterially and liposomal doxorubicin (doxil) 20–35 mg/m² IV (day 1) every 28 days. A “3 + 3” study design was used.

Results

Thirty patients were treated (median age, 56 years). Diagnoses were breast cancer (n = 11), colorectal cancer (n = 8), ocular melanoma (n = 4), and other (n = 7). The median number of prior therapies was 5. The maximum tolerated dose (MTD) was at the 100/35 mg/m² level. Dose-limiting toxicities were Grade 4 neutropenia (2 of 4 patients), and Grade 4 thrombocytopenia (n = 1) at the cisplatin 125 mg/m² and systemic doxil 35 mg/m² dose level. The most common toxicities were nausea/vomiting and fatigue. Of 24 patients evaluable for response, 4 (17%) had a partial response (PR) and 7 (29%) had stable disease (SD) for ≥4 months. Of the 11 patients with breast cancer, 3 (27%) had a PR and 5 (45%) had SD for ≥4 months. Of 4 patients with ocular melanoma, 1 had a PR and 1 SD for 4 months. One patient with hepatocellular carcinoma had SD for 4 months. Of 12 evaluable patients treated at the MTD, 2 (17%) had a PR and 5 (42%) had SD.

Conclusion

The MTD was HAI cisplatin 100 mg/m² and systemic doxil 35 mg/m². This regimen demonstrated antitumor activity, especially in breast cancer.     

A phase I study of the biomodulation of capecitabine by docetaxel and gemcitabine (mGTX) in previously untreated patients with metastatic adenocarcinoma of the pancreas

Background

Pancreas cancer remains a formidable challenge. We report the first prospective analysis of the 3-drug combination of gemcitabine (G), docetaxel (T) and capecitabine (X) (mGTX) with schedule modification to maximize biomodulation of X.

Methods

We conducted a dose escalation study of mGTX in first-line treatment of metastatic pancreas cancer using three dose levels (DL 1-3). Patients received docetaxel on days 1 and 8, gemcitabine on days 8 and 15, and capecitabine on days 8 through 21. Gemcitabine dose was fixed at 750?mg/m² over 75?min, capecitabine was given twice daily and escalated from 500 to 650?mg/m² at DL2 and docetaxel increased from 30 to 36?mg/m² at DL3.

Results

Twenty-one patients (18 evaluable) were enrolled in the study. MTD was reached at DL3 and one DLT was observed at DL2 (prolonged neutropenia). The most common grade 3/4 toxicities were leukopenia (29%) and neutropenia (29%) and fatigue (25%). Tumor growth control rate was 80% (11% PR; 69% SD lasting at least 3?months). Median progression-free-survival was 5.8?months (95% CI 2.7, 10.6) and median overall survival was 7.4?months (95% CI 3.8 16.8). CA 19-9 decreased by at least 50% from baseline in half the patients.

Conclusion

mGTX demonstrates acceptable tolerability with interesting activity in patients with pancreatic cancer. The recommended doses for phase II studies are docetaxel 36?mg/m² days 1 and 8, gemcitabine 750?mg/m² over 75?min days 8 and 15, and capecitabine 625?mg/m² twice daily days 8 through 21.