Second-line Chemotherapy In Patients Research Articles

Phase I study of bevacizumab combined with irinotecan and S-1 as second-line chemotherapy in patients with advanced colorectal cancer

The combination of an oral fluoropyrimidine derivative, S-1, and irinotecan has been reported to be a promising regimen for advanced colorectal cancer. However, the safety and efficacy of bevacizumab (BV) to combine with irinotecan and S-1 has not been determined. The aim of the study was to determine the maximum tolerated dose (MTD) and recommended dose (RD) of BV combined with irinotecan plus S-1, and to observe the safety and efficacy of this regimen as second-line chemotherapy in patients with advanced colorectal cancer. This study initially had been planned as a phase I/II study. Eighty mg/m(2) of irinotecan on days 1 and 8, 80 mg/m(2) of S-1 for 14 consecutive days, and two doses of BV (Level 1; 10 mg/kg, Level -1; 7.5 mg/kg) were administered on day 1 every 3 weeks. Fourteen patients were enrolled in phase I of the study between January 2008 and September 2010. Dose-limiting toxicities were diarrhea, abdominal pain, and infection. The MTD and RD of BV were determined to be 10 mg/kg and 7.5 mg/kg, respectively. The main adverse events were leukopenia, anorexia, and diarrhea. There were no treatment-related deaths. An independent review committee was scheduled to evaluate safety in phase I, but this trial closed early due to toxicity. This study identified the risk of gastrointestinal toxicity with the combination of irinotecan, S-1 and BV as second-line chemotherapy in patients with advanced colorectal cancer.

Gemcitabine Plus Paclitaxel as Second-line Chemotherapy in Patients with Advanced Non-Small Cell Lung Cancer

The aim of this retrospective study was to determine response rates, progression-free survival (PFS), overall survival (OS) and toxicity of gemcitabine and paclitaxel combinations with advanced or metastatic non-small cell lung cancer patients (NSCLC) who have progressive disease after platinum-based first-line chemotherapy. We retrospectively evaluated the file records of patients treated with gemcitabine plus paclitaxel in advanced or metastatic NSCLC cases in a second-line setting. The chemotherapy schedule was as follows: gemcitabine 1500 mg/m2 and paclitaxel 150 mg/m2 administered every two weeks. Forty-eight patients (45 male, 3 female) were evaluated; stage IIIB/IV 6/42; PS0, 8.3%, PS1, 72.9%, PS2, 18.8%; median age, 56 years old (range 38-76). Six (12.5%) patients showed a partial response (PR), 13 (27.1%) stable disease (SD), and 27 (56.3%) progressive disease (PD). The median OS was 6.63 months (95% CI 4.0-9.2); the median PFS was 2.7 months (95% CI 1.8-3.6). Grade 3 and 4 hematologic toxicities, including neutropenia (n=4, 8.4%), and anemia (n=3, 6.3%) were encountered, but no grade 3 or 4 thrombocytopenia. One patient developed febrile neutropenia. There were no interruption for reasons of toxicity and no exitus related to therapy. The combination of two-weekly gemcitabine plus paclitaxel was an effective and well-tolerated second-line chemotherapy regimen for advanced or metastatic NSCLC patients previously treated with platinum-containing chemotherapy. Although the most common and dose limiting toxicities were neutropenia and neuropathy, this regimen was tolerated well by the patients.

O2-058 - Efficacy and Safety of S-1 as Second-Line Chemotherapy for Patients with Advanced Biliary Tract Cancer

ABSTRACT Background Gemcitabine (GEM) was widely used, and cisplatin plus GEM is considered as a standard first-line chemotherapy for patients with advanced biliary tract cancer (BTC). However, no standard therapy was established following the progression to GEM-contained first-line therapy. And S-1 monotherapy as second-line chemotherapy is still not well known in practice medicine. Object We retrospectively reviewed 55 consecutive patients who received S-1 monotherapy as second-line chemotherapy after the failure to GEM-contained regimen at our institution between September 2007 and March 2011. The key inclusion criteria were with preserved organ function and ECOG PS 0-2 and without massive ascites or pleural effusion. S-1 was administered orally twice a day at a dose of 40 mg/m2 for 28 days, followed by 14 days of rest. Results Fifty-one patients were selected for this analysis. The overall response rate was 4.0% and the disease control rate was 38.0%. The median survival time was 6.0 months and the median progression-free survival was 2.3 months. Grade 3/4 toxic effects were diarrhea (6%), leucopenia (2%), neutropenia (2%), anemia (2%), thrombocytopenia (2%), nausea (2%), mucositis (2%), and skin rash (2%). No treatment death was occured. Conclusion S-1 monotherapy is well tolerated and moderately efficacious in the second-line chemotherapy for patients with GEM-refractory advanced BTC in practice. However, advanced BTC consist of plural disease and its background is different from each other; randomized control study is needed.

P3-122 - Second-Line Therapy on Cancer of Unknown Primary in Unfavorable-Risk Patients

ABSTRACT Purpose There are few reports on the efficacy of second-line chemotherapy in patients with cancer of unknown primary site (CUP). We tried to reveal the effectiveness of second-line chemotherapy on CUP patients. Methods We retrospectively analyzed the clinical outcomes of second-line chemotherapy in patients with CUP of the unfavorable-risk group. Results Among 110 CUP patients between May 2002 and January 2012, unfavorable-risk patients are 67 patients. Total of 32 patients (48% of unfavorable-risk patients) were able to receive second-line chemotherapy. Of these patients, 6 (19%) showed an objective partial response to second-line chemotherapy, 15 (48%) showed stable disease response after receiving second-line chemotherapy. Median progression-free survival of second-line therapy is 90 days (range; 11–503). Mean overall survival is 366 days (range; 138–1676) in 32 unfavorable-risk CUP patients who could receive second-line chemotherapy; however, 106 days (range; 5–787) in 28 patients who could not receive. Among the 32 patients who could receive second-line chemotherapy, these who responded first-line chemotherapy (first-line chemotherapy most response; PR or SD) may be favorable progression-free survival in second-line chemotherapy (P = 0.0398). Conclusion Second-line chemotherapy may be beneficent for unfavorable-risk CUP patients who had good response to first-line chemotherapy.

IS3-6 - Multicenter Randomized Phase II Study of Weekly Docetaxel Alone Versus Weekly Docetaxel Plus Oxaliplatin as a Second-Line Chemotherapy in Patients with Advanced Gastric Cancer: Preliminary Response and Safety Results

ABSTRACT Background Gastric cancer is a frequent malignancy with worldwide estimated incidence of 990'000 cases, representing 7.8% of all cancers in 2008. There are limited data suggesting a benefit for doublet second-line chemotherapy in advanced gastric cancer. Methods The eligibility criteria were patients 1) with prior exposure to cisplatin based chemotherapy and advanced or recurrent stomach cancer 2) with pathologically proven gastric adenocarcinoma, 3) with an ECOG performance status 0 to 2, 4) with measurable lesions. Each treatment cycle was consisted of docetaxel 36 mg/m2 in docetaxel mono therapy group and docetaxel 36 mg/m2, oxaliplatin 80 mg/m2 in docetaxel/oxaliplatin doublet therapy group on days 1, 8. The primary end point of this study was response rate, and secondary end points included toxicity, progression free and overall survival. Results Fifty two patients were enrolled; median age was 63 years; male (n = 42) and female (n = 10); docetaxel mono therapy (n = 27) and docetaxel/oxalliplatin doublet therapy (n = 25). The median number of cycles administered was 2.5 (range,1-9). Fourty eight patients were assessable for efficacy. Four partial responses, 7 stable diseases in mono therapy group (RR; 4/27, 14.8%) and 1 complete remission, 4 partial responses, 13 stable diseases in double therapy group (RR; 5/25, 20.0%) were confirmed (P = 0.198). Median progression free survival was 1.97 months in the mono therapy group and 4.93 months in doublet therapy group (P = 0.007). Median overall survival was 11.57 months in the mono therapy group and 8.13 months in doublet therapy group (P = 0.650). Grade 3 or 4 adverse events were reported in 11 of 52 patients; G3 pain were in 2 patients and G3 pneumonia was in 1 patient in mono group, G3/4 neutropenia were 5 patients in the combination group, G3 nausea, vomiting, general weakness was 1 patient each group in combination group. Conclusions Weekly docetaxel/oxaliplatin doublet therapy showed superior progression free survival to monotherapy group as second line therapy in cisplatin pretreated advanced gastric cancer patients.

O1-002 - Correlation Between the Effects of First-Line Chemotherapy and Survival Time from Second-Line Chemotherapy in Patients with Advanced Gastric Cancer

ABSTRACT Background In advanced gastric cancer (AGC), several prognostic factors for survival time in first-line chemotherapy (1st-CTX) have been reported. However, there are few reports about the relationship between the effects of 1st-CTX and survival time from the start of 2nd-CTX (2nd-MST). Objectives To evaluate between the effects of S-1 + CDDP (SP) therapy as 1st-CTX and 2nd-MST in patients with AGC. Patients and methods The subjects were 32 patients who were treated with SP therapy as 1st-CTX between October 2002 and December 2010 at our institute. The main selection criteria were as follows: with measurable lesions, treated with Irinotecan (CPT-11) or weekly Paclitaxel (wTXL) as 2nd-CTX. Univariate and multivariate analyses were carried out to examine the correlation between 2nd-MST and the efficacy of SP therapy (progression free survival: 1st-PFS, best tumor response rate: best-RR, time to best response) and other prognostic factors. Results The median survival time (1st-MST) and 1st-PFS was 425 and 206 days, respectively. The RR in SP therapy was 66% (PR 21 patients). Best-RR was 30–40/41–50/51–60/61–70/ > 71, %:4/4/3/8/2 patients, respectively. The median to best response time was 73 days. The patient characteristics at the start of 2nd-CTX were as follows: the median age; 63 years, PS; 0/1/2: 9/13/10, histology; intestinal type/diffuse type; 19/13, number of organs with metastases; 1/2/ > 3: 6/16/10, lymph node metastases; yes/no: 20/12, peritoneal dissemination; yes/no: 15/17, 2nd-CTX; CPT/wTXL: 18/14. The 2nd-MST was 173 days. The following factors were correlated with longer 2nd-MST by univariate analyses; age ( Conclusions The effect of SP therapy as 1st-CTX is not prognostic factor of 2nd-MST.

Methotrexate-paclitaxel-epirubicin-carboplatin as second-line chemotherapy in patients with metastatic transitional cell carcinoma of the bladder pretreated with cisplatin-gemcitabine: A phase II study

To assess the efficacy and toxicity of methotrexate-paclitaxel-epirubicin-carboplatin combination as second-line chemotherapy in patients with metastatic transitional cell carcinoma (TCC) of the bladder pretreated with cisplatin-gemcitabine. In this prospective phase II study, patients with metastatic TCC of the bladder pretreated with first-line cisplatin-gemcitabine received on progression paclitaxel 175 mg/m(2) i.v. and carboplatin (area under curve of 5) on day 1, and methotrexate 40 mg/m(2) and epirubicin 40 mg/m(2) on day 15. The whole course was repeated every 28 days. The end-points included clinical tumor response, treatment toxicity, quality of life and survival. A total of 40, predominantly male, patients were enrolled (median age 62 years [range 46-69]). Efficacy and survival were assessed in 38 patients only, as two patients refused treatment after the first cycle. Grade 3 neutropenia was the commonest acute severe toxicity (12/40 patients; 30%). The overall response rate was 39% (15/38 patients). The median follow up was 14 months (range 3-45). The median progression-free and overall survival were 12 and 12.5 months, respectively. The 1-year progression-free and overall survival were 24 and 35%, respectively. Methotrexate-paclitaxel-epirubicin-carboplatin combination as second-line chemotherapy in patients with metastatic TCC of the bladder results in a modest response rate with acceptable toxicity.

A Retrospective Study of S-1 Monotherapy as Second-line Treatment for Patients with Advanced Biliary Tract Cancer

Gemcitabine has been widely used, and cisplatin plus gemcitabine is considered as standard first-line chemotherapy for patients with advanced biliary tract cancer. However, no standard therapy was established following the progression to gemcitabine-containing first-line therapy. As S-1 monotherapy as second-line chemotherapy is still not well known in a practical setting this study aimed to clarify its efficacy and safety. We retrospectively reviewed 55 consecutive patients who received S-1 monotherapy as second-line chemotherapy after failure of a gemcitabine-containing regimen at our institution from September 2007 to March 2011. The inclusion criteria were preserved organ function and an Eastern Cooperative Oncology Group performance status of 0-2 and without massive ascites or pleural effusion. S-1 was administered orally twice a day at a dose of 40 mg/m(2) for 28 days, followed by 14 days of rest. Fifty-one patients were selected for this analysis. The overall response rate was 4.0% and the disease control rate was 38.0%. The median survival time was 6.0 months and the median progression-free survival was 2.3 months. Adverse events were generally mild, and treatment-related death did not occur. In the subgroup analysis, overall survival was significantly shorter in the patients with peritoneal dissemination and those who had shown no response to the first-line chemotherapy (P= 0.033 and 0.023, respectively). S-1 monotherapy as the second-line chemotherapy for patients with gemcitabine-refractory advanced biliary tract cancer is also feasible in a practical setting and its efficacy is almost the same as in the previous prospective study.

Multicenter randomized phase II study of weekly docetaxel alone versus weekly docetaxel plus oxaliplatin as a second-line chemotherapy in patients with advanced gastric cancer: Preliminary response and safety results.

e14570 Background: Gastric cancer is a frequent malignancy with worldwide estimated incidence of 990,000 cases, representing 7.8% of all cancers in 2008. There are limited data suggesting a benefit for doublet second-line chemotherapy in advanced gastric cancer. Methods: The eligibility criteria were patients 1) with prior exposure to cisplatin based chemotherapy and advanced or recurrent stomach cancer 2) with pathologically proven gastric adenocarcinoma, 3) with an ECOG performance status 0 to 2, 4) with measurable lesions. Each treatment cycle was consisted of docetaxel 36 mg/m2 in docetaxel mono therapy group and docetaxel 36 mg/m2, oxaliplatin 80 mg/m2 in docetaxel/oxaliplatin doublet therapy group on days 1, 8. The primary end point of this study was response rate, and secondary end points included toxicity, progression free and overall survival. Results: Fifty two patients were enrolled; median age was 63 years; male (n=42) and female (n=10); docetaxel mono therapy (n=27) and docetaxel/oxalliplatin doublet therapy (n=25). The median number of cycles administered was 2.5 (range,1-9). Fourty eight patients were assessable for efficacy. Four partial responses, 7 stable diseases in mono therapy group (RR; 4/27, 14.8%) and 1 complete remission, 4 partial responses, 13 stable diseases in double therapy group (RR; 5/25, 20.0%) were confirmed (p=0.198). Median progression free survival was 1.97 months in the mono therapy group and 4.93 months in doublet therapy group (p=0.007). Median overall survival was 11.57 months in the mono therapy group and 8.13 months in doublet therapy group (p=0.650). Grade 3 or 4 adverse events were reported in 11 of 52 patients; G3 pain were in 2 patients and G3 pneumonia was in 1 patient in mono group, G3/4 neutropenia were 5 patients in the combination group, G3 nausea, vomiting, general weakness was 1 patient each group in combination group. Conclusions: Weekly docetaxel/oxaliplatin doublet therapy showed superior progression free survival to monotherapy group as second line therapy in cisplatin pretreated advanced gastric cancer patients.

Combined analysis of randomized controlled trial (RCT) and patient-preference trial (PPT) evaluating second-line chemotherapy (SLC) in advanced gastric cancer (AGC).

4064 Background: While prolonged overall survival (OS) from SLC compared to best supportive care (BSC) has recently been demonstrated for AGC (Park et al, ASCO 2011), the prognosis of pretreated AGC remains poor. We assessed whether patient preference, willing to participate onto RCT, or other parameters contributed to this OS improvement. Methods: In the phase III trial, pretreated AGC patients (n=372) were first offered RCT. If a patient agreed to participate, randomly assigned 2:1 to SLC or BSC (n=202). If refused RCT, but agreed to receive treatment of their preference, they were offered SLC or BSC (PPT; n=170). OS of RCT participants was compared to that of whole patient population according to prognostic subgroups. In addition, analyses of OS unadjusted for multiple comparisons were conducted across predefined subgroups. Results: Median OS was 6.3 months among 254 patients treated with SLC and 3.3 months among 118 patients treated with BSC (HR, 0.507; 95% CI, 0.405 to 0.637; one-sided p<0.001). Compared to the RCT patients, younger age group, those with an ECOG performance status (PS) of 0, and with one prior chemotherapy were under-represented in the PPT patients. OS was comparable between RCT (5.0 months) and PPT (4.4 months) patients even after controlling for major prognostic factors (log-rank p=0.322). The OS benefit for SLC was preserved when analyzed according to baseline parameters. Parameters that were associated significantly with a prolonged OS included a PS of 0, the chemotherapy-free interval ≥3 months, and one prior chemotherapy. When the analysis was adjusted for these three parameters, patients who received SLC still had improved OS (HR, 0.554; 95% CI, 0.441 to 0.696; p<0.001). Conclusions: The 54% participation rate obtained in the current study represents the best achievable rate for this kind of phase III RCT involving BSC only arm. Even if we consider differences in the baseline characteristics between RCT and PPT patients, it is concluded that the RCT results can be generalized for the patient population and provided additional evidence supporting the use of SLC in patients with pretreated AGC.

Correlation between overall survival and other endpoints in clinical trials of second-line chemotherapy for patients with advanced gastric cancer.

4067 Background: The correlation between progression-free survival (PFS) or time to progression (TTP) and overall survival (OS) has been evaluated in patients with advanced gastric cancer (AGC) who received first-line chemotherapy (Shitara, K et al. Invest New Drug 2011; Shitara K and Burzykowski T, et al, ASCO 2011). However, no corresponding analysis had been done in patients who underwent second-line chemotherapy for AGC. Methods: We evaluated the potential of PFS, TTP, response rate (RR), or disease control rate (DCR) to act as surrogates for OS in phase II and III trials of second-line chemotherapy for AGC by comprehensive literature-based analysis. Correlations between each endpoint and OS were evaluated by Spearman rank correlation coefficient (ρ). Subgroup analyses by trial region or type of failure to previous chemotherapy were also conducted. Results: Fifty-six trials, including four randomized studies, were selected for analysis and covered a total of 61 treatment arms and 3,038 patients; 34 studies were conducted in Asia, 20 studies in Non-Asian countries, and two studies in both regions. Median PFS were similar in Asian and Non-Asian trials (3.0 vs. 3.3 months). In contrast, median OS tended to be longer in Asian vs. Non-Asian trials (8.0 vs. 6.0 months; p<0.01). Median PFS/TTP and OS showed a moderate correlation with ρ of 0.51 (95% CI, 0.31-0.73). Correlation tended to be higher in PFS (ρ = 0.62) than TTP (ρ = 0.29) and higher in non-Asian trials (ρ = 0.73) than Asian trials (ρ = 0.32). Correlation between PFS/TTP and OS among the trials in which eligibility required failure to previous fluorouracil and cisplatin also showed low correlation (ρ = 0.48). The RR and DCR also did not show high correlation with OS (ρ = 0.30 for RR; 95% CI 0.04-0.56; ρ = 0.53 for DCR; 95% CI 0.31-0.75). The hazard ratio (HR) of PFS and OS in each arms of the four randomized studies showed a low correlation with ρ of 0.10. Conclusions: Our results indicate that PFS/TTP, RR, and DCR did not correlate sufficiently with OS to be used as surrogate endpoints in patients with AGC who underwent second-line chemotherapy. Further research is needed based on individual patient data from ongoing randomized trials.

FOLFIRI as second-line chemotherapy for advanced pancreatic cancer: a GISCAD multicenter phase II study

The purpose of the present study was to evaluate the activity and the tolerability of the FOLFIRI regimen, administered as second-line chemotherapy in patients with locally advanced or metastatic pancreatic cancer after the failure of a gemcitabine-based regimen. Patients with locally advanced/metastatic disease who received a first-line chemotherapy (one line only) with gemcitabine ± platinoid (cisplatin, oxaliplatin) and who had measurable disease conform with the RECIST criteria were eligible for the study. FOLFIRI consists of irinotecan 180 mg/m(2) i.v. on day 1, leucovorin (l-form) 200 mg/m(2) i.v. on day 1 and 2, 5-FU 400 mg/m(2) i.v. bolus on days 1 and 2, and 5-FU 600 mg/m(2) i.v. by ci for 22 h on days 1 and 2, repeated every 2 weeks. The primary end point was the response rate. Among the 50 enrolled patients, 4 partial responses (PR) (8%) and 14 stable diseases were observed, for a disease control rate of 18/50 (36%). Forty-one patients (82%) have been pretreated with cisplatin/oxaliplatin+gemcitabine as first-line chemotherapy. The median progression-free and overall survivals were 3.2 and 5 months, respectively. The 6-month survival rate was 32%. Grade 3-4 neutropenia and diarrhea occurred in 10 (20%) and 6 (12%) patients, respectively. The FOLFIRI regimen showed a modest clinical activity in this quite heavily pretreated patients' population with locally advanced or metastatic pancreatic cancer with a manageable toxicity profile.

Gemcitabine and Paclitaxel Combination as Second-Line Chemotherapy in Patients With Small-Cell Lung Cancer: A Phase II Study

BackgroundAlthough small-cell lung cancer is a chemosensitive malignancy, most patients rapidly relapse. Results of second-line treatment are generally poor. We conducted a phase II study to evaluate the activity and toxicity of a combination of gemcitabine and paclitaxel as second-line chemotherapy. Patients and MethodsEligible patients were refractory or relapsed small-cell lung cancer, with an Eastern Cooperative Oncology Group performance status of 0-2 and measurable disease. Paclitaxel was administered at 135 mg/m2 days 1 and 8 immediately followed by gemcitabine at 1000 mg/m2 every 3 weeks up to 6 courses. Restaging of disease was scheduled every 3 courses. ResultsForty-one patients were enrolled. The median age was 65 years. Nineteen patients were considered refractory (progressive disease during or within 90 days from completion of first-line treatment), whereas 22 patients were chemotherapy sensitive. A total of 135 courses was administered (range, 1-6; median, 3). Nine patients achieved a partial remission (partial response, 22%), and 10 patients had stable disease (24%), with a disease control rate (partial response + stable disease) of 46%: in 12 (55%) of 22 patients who were sensitive and in 7 (37%) of 19 patients with refractory disease, respectively. All partial responses but one were observed in the sensitive group. The median duration of response was 5 months. The most-frequent severe toxicities were neutropenia grade 3-4 and neurologic grade 3 in 24% and 7% of delivered courses, respectively. ConclusionsThe combination of gemcitabine and paclitaxel investigated in our study achieved a high disease control rate, but the schedule we adopted appeared to be quite toxic.

Second-line bevacizumab-containing therapy in patients with triple-negative breast cancer: subgroup analysis of the RIBBON-2 trial

Patients with metastatic triple-negative breast cancer (TNBC) typically have a poor prognosis and limited treatment options. To determine the impact of combining bevacizumab with second-line chemotherapy in patients with metastatic TNBC, we performed an exploratory subgroup analysis of the randomized phase 3 RIBBON-2 trial. RIBBON-2 enrolled patients with metastatic breast cancer that had progressed on first-line non-bevacizumab-containing chemotherapy. After selection of chemotherapy (taxane, gemcitabine, capecitabine, or vinorelbine), patients were randomized 2:1 to receive chemotherapy with either bevacizumab (10 mg/kg every 2 weeks or 15 mg/kg every 3 weeks) or placebo. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), and safety. Of 684 patients treated in RIBBON-2, 159 (23%) had TNBC. Baseline characteristics were reasonably balanced in the two treatment groups. The majority received taxane chemotherapy. The hazard ratio (HR) for PFS was 0.494 [95% confidence interval (CI) 0.33-0.74; P = 0.0006]. Median PFS was 6.0 months with bevacizumab-chemotherapy versus 2.7 months with chemotherapy alone. Median OS was 17.9 versus 12.6 months, respectively (HR 0.624, 95% CI 0.39-1.007; P = 0.0534). ORR was 41 versus 18%, respectively (P = 0.0078). The safety profile was consistent with the overall study population and previous phase 3 trials of bevacizumab. Patients with metastatic TNBC derived significant PFS and response benefits from the combination of bevacizumab with second-line chemotherapy. Despite the small sample size and immature data, there was a trend toward improved OS.

230 A Phase II Study of Pegylated Liposomal Doxorubicin Combined with Cyclophosphamide / 5-fluorouracil as Second Line Chemotherapy in Patients with Metastatic Breast Cancer Who Failed Previous Taxane-based Treatment

230 A Phase II Study of Pegylated Liposomal Doxorubicin Combined with Cyclophosphamide / 5-fluorouracil as Second Line Chemotherapy in Patients with Metastatic Breast Cancer Who Failed Previous Taxane-based Treatment

Feasibility and potential benefits of second-line chemotherapy in patients with advanced biliary tract cancer.

338 Background: Chemotherapy is effective in metastatic or unresectable biliary tract cancer (BTC). The benefits of second-line chemotherapy (CT2) are unclear. Methods: We retrospectively studied all patients (pts) receiving at least one cycle of chemotherapy for advanced BTC at our institution between 1991 and 2011. We analyzed pt and chemotherapy characteristics (type of regimen; tumor response; time to progression (TTP); and overall survival (OS)). The objectives were: 1) to characterize pts eligible for CT2; 2) to evaluate the efficacy of CT2. Results: 367, 89 (24%), and 24 (6%) pts received CT1, CT2, and CT3, respectively. Primary tumor location was the gallbladder (30%), intraphepatic (16%), perihilar (20%), distal common bile duct (20%), and ampulla of Vater (14%). 88% had a baseline performance status of 0-1 prior to CT1. The regimen and efficacy data of CT1 and CT2 are presented in the Table . On univariate analysis females (p=0.002) and pts with TTP >6 months on CT1 (p=0.016) were the only variables associated with receiving CT2. The only factor associated with disease control (objective response+ stable disease) on CT2 was the regimen type (75% with a doublet versus 46% with monotherapy, p=0.03). Conclusions: Among patients with advanced BTC treated with chemotherapy, less than 25% received CT2; but responses were seen and were surprisingly high even in this selected population. Pts with a longer TTP on CT1 were more likely to be offered CT2. Better disease control with CT2 occurs with a doublet than single agent, however clearly more effective therapies must be found. Updated data will be presented. [Table: see text]

Phase II clinical trial of second-line FOLFIRI plus bevacizumab for patients with metastatic colorectal cancer: AVASIRI trial

FOLFIRI is a standard chemotherapy regimen for the treatment of metastatic colorectal cancer. Although some studies have shown its efficacy in combination with bevacizumab as first-line chemotherapy, there are no data to support FOLFIRI plus bevacizumab as second-line chemotherapy in patients with this form of cancer. The aim of this study was to evaluate the efficacy and safety of FOLFIRI and bevacizumab as second-line chemotherapy in patients with metastatic colorectal cancer. Eligible patients were ≥20 years old, previously treated (except with irinotecan [CPT-11] and bevacizumab), with an Eastern Cooperative Oncology Group performance status of 0, 1, or 2, and adequate organ function. Twenty-five eligible patients received FOLFIRI with bevacizumab at a dose of 10 mg/kg given intravenously on day 1. All therapy was administered every 2 weeks until disease progression. The primary endpoint was the response rate. Twenty-five patients were enrolled between February 2008 and March 2009. The median age was 62 (range 38-73) years, the male/female distribution was 20/5, 16 patients had performance status 0 and 9 had performance status 1, and the proportion of patients who were oxaliplatin pretreated/untreated was 16/9. The overall response rate was 32% (90% confidence interval [CI]: 17.0-50.4%), with 8 patients showing partial responses, 15 with stable disease, and 2 with disease progression. Median progression-free survival was 11.6 months (95% CI: 6.9-16.4). Median overall survival was 21.4 months (95% CI: 12.0-30.8). The grade 3/4 adverse events with treatment were neutropenia (64%), leukopenia (16%), diarrhea (8%), anorexia (8%), and febrile neutropenia (8%). The bevacizumab-related grade 3/4 adverse event was hypertension, which was observed in 12% of patients. The FOLFIRI plus bevacizumab regimen is an active, well-tolerated second-line chemotherapy treatment for patients with metastatic colorectal cancer.

Effects of S-1 as a second-line chemotherapy for patients with relapsed pancreatic cancer

Adjuvant chemotherapy with gemcitabine is the standard treatment in Japan for patients who have undergone resection of pancreatic cancer. However, few reports have described suitable regimens for patients who present cancer relapse following adjuvant chemotherapy. In the present study, we retrospectively evaluated the efficacy and safety of S-1, an oral fluoropyrimidine derivative, as a second-line chemotherapy for patients who had suffered relapse of pancreatic cancer following adjuvant chemotherapy with gemcitabine. A total of 51 patients with pancreatic cancer suffered relapse after curative resection and subsequent adjuvant chemotherapy with gemcitabine at our institution. A group of 26 of these patients were administered S-1 orally twice daily after meals at a dose of 80 mg/m(2) for body surface areas for 14 consecutive days, followed by a 7-day rest (S-1 group). The remaining 25 patients received no additional anticancer drugs other than continuation of gemcitabine (GEM/BSC group). During a median follow-up period of 35 months, a significant difference was observed in overall survival (OAS) between the S-1 group and the control group (median OAS, 20.9 vs. 13.7 months; p=0.0157, log-rank test). Furthermore, there was a significant inter-group difference in survival after relapse (SAR) (median SAR, 11.4 vs. 6.20 months; p=0.0025, log-rank test). No increase in grade 3/4 hematological and non-hematological toxicity was observed in the S-1 group. In conclusion, second-line chemotherapy using a combination of S-1 and adjuvant chemotherapy with gemcitabine may be an efficient and beneficial strategy for patients with relapsed pancreatic cancer.

5-Fluorouracil/Leucovorin Combined with Irinotecan and Oxaliplatin (FOLFIRINOX) as Second-Line Chemotherapy in Patients with Metastatic Pancreatic Adenocarcinoma

Background: To evaluate the efficacy and toxicity of irinotecan and oxaliplatin plus 5-fluorouracil (FU) and leucovorin (FOLFIRINOX) as second-line therapy in metastatic pancreatic adenocarcinoma (MPA). Patients and Methods: We retrospectively analyzed the medical records of 27 patients with MPA treated with FOLFIRINOX as second-line therapy between January 2003 and November 2009 in our hospital. The recommended schedule was oxaliplatin 85 mg/m² on day 1 + irinotecan 180 mg/m² on day 1 + leucovorin 400 mg/m² on day 1 followed by FU 400 mg/m² as a bolus on day 1 and 2,400 mg/m² as 46-hour continuous infusion biweekly. Results: The median age of the 27 patients (13 males and 14 females) was 63 years (45–83). All patients had progressive disease after first-line chemotherapy by gemcitabine. A total of 167 cycles were administered, with a median number of 6 cycles (1–29) per patient. One toxic death occurred (sepsis). Tolerance of treatment was acceptable, and the relative dose density delivered per patient was 92.8% for oxaliplatin, 89.1% for irinotecan and 96.4% for FU. Grade 3–4 neutropenia occurred in 55.6% of the patients, including 1 febrile neutropenia. The other toxicities were manageable. Regarding efficacy, 22 of the 27 patients were evaluable (WHO and RECIST criteria). Five patients had partial responses and 12 stable disease, resulting in an overall disease control rate of 63%. Median time to progression was 5.4 months (0.7–25.48), and median event-free survival was 3 months (0.5–24.9). Median overall survival was 8.5 months (0–26). A clinical benefit was reported for 55% of the patients. Conclusions: These results confirmed the good safety profile and the efficacy of the FOLFIRINOX regimen as second-line treatment of MPA.

Management strategies for recurrent platinum-resistant ovarian cancer.

Although ovarian cancer is often a chemosensitive malignancy, patients who are resistant to platinum-based chemotherapy represent a therapeutic challenge. Currently, the only drugs that are US FDA approved to treat this subset of patients are paclitaxel, pegylated liposomal doxorubicin (PLD) and topotecan. The response rates with these agents is in the 10-15% range and overall survival is around 12 months. Other drugs that have shown some activity in platinum-resistant ovarian cancer include the taxane analogues, oral etoposide, pemetrexed and bevacizumab. Unfortunately, randomized phase III trials of second-line chemotherapy in patients with platinum-resistant ovarian cancer have not shown an advantage over existing therapy with respect to progression-free survival or overall survival. The only trial that has reported a significant progression-free survival advantage over standard therapy is a randomized phase II trial of PLD with or without EC145, a folate-linked vinca alkaloid. Final survival results of this trial are pending.