Phase II study of S-1 monotherapy in patients with previously treated, advanced non-small-cell lung cancer

Background

In this phase II clinical trial, we evaluated the efficacy and safety of S-1 monotherapy in patients with previously treated advanced non-small-cell lung cancer (NSCLC). We also measured plasma concentrations of 5-fluorouracil (5-FU) and 5-chloro-2,4-dihydroxypyridine components of S-1 and examined correlation with effectiveness and toxicity.

Methods

S-1 was given orally at a dose of 80?mg/m²/day for 14 consecutive days, followed by a 7-day rest period. This treatment course was repeated until disease progression or intolerable toxicity.

Results

We enrolled 30 patients. The response rate was 26.7% (8/30), and the disease control rate was 70% (21/30). Median progression-free survival (PFS) was 3.1?months, and median overall survival (OS) was 11.2?months. Mutations in the epidermal growth factor receptor (EGFR) gene were analyzed in 27 patients. The response rate was higher in patients with mutant EGFR (50.0%) than in those with wild-type EGFR (11.8%, P?=?0.0288). Median PFS was 4.8 and 2.5?months (P?=?0.038), and median OS was 22.4 and 8.4?months (P?=?0.071). There was no grade 4 toxicity in this study. Five patients had grade 3 non-hematologic toxicity, and there was a trend toward higher plasma concentrations of 5-FU in those patients than in another patients.

Conclusions

S-1 monotherapy is effective and well-tolerated treatment for previously treated advanced NSCLC.     

Retrospective analysis of cetuximab monotherapy for patients with irinotecan-intolerant metastatic colorectal cancer

Background

The efficacy and safety of cetuximab for irinotecan-intolerant patients has not yet been evaluated in detail.

Methods

We retrospectively analyzed the efficacy and safety of cetuximab monotherapy for patients with metastatic colorectal cancer (MCRC) that was intolerant to irinotecan.

Results

Among 105 patients who received cetuximab-containing chemotherapy until March 2010, 22 patients were treated with cetuximab monotherapy due to irinotecan intolerance. Cetuximab was given at the approved dosage to all patients. The performance status was 2 or 3 in 17 patients (77%). All but 1 patient had wild-type KRAS tumors. The causes of irinotecan intolerance were icterus (n?=?9; 41%; median serum total bilirubin, 6.3?mg/dl), symptomatic peritoneal metastasis or obstruction (n?=?8; 36%), and thrombocytopenia (n?=?1; 5%). Four patients (18%) refused irinotecan due to previous irinotecan-associated toxicity. Two patients achieved a partial response with an apparent drop of serum bilirubin, for a response rate of 9.1%. The median progression-free survival and overall survival were 1.6 and 3.5?months, respectively. No grade 3 or 4 adverse events or treatment-related deaths were experienced.

Conclusion

Cetuximab monotherapy for irinotecan-intolerant MCRC is feasible. However, the overall efficacy was modest in the present cohort, despite the fact that most of the patients had wild-type KRAS tumors; further effective therapies should be evaluated to improve the prognosis of this patient population.     

Phase I/II study of S-1 combined with biweekly irinotecan chemotherapy in previously treated advanced non-small cell lung cancer

Purpose

This phase I/II study was designed to evaluate a combination of irinotecan and S-1 a new regimen for salvage chemotherapy in patients with advanced or metastatic non-small cell lung cancer (NSCLC).

Methods

The study group comprised patients with advanced or metastatic NSCLC who had previously received at least one platinum-containing chemotherapy. Patients received irinotecan on days 1, 15 and oral S-1 (40?mg/m² twice daily as a fixed dose) on day 1 to 14 of a 28-day cycle.

Results

In the phase I part, irinotecan was given in escalating doses of 70 (Level 1), 80 (Level 2), and 90?mg/m² (Level 3). Three of the 5 patients given Level 3 had dose-limiting toxicity, and Level 2 (80?mg/m² of irinotecan) was designated as the recommended dose. In phase II, 38 patients received a median of 7.4 cycles of irinotecan at the recommended dose. The overall response rate was 15.8?% (90?% confidence interval (CI): 6.1–25.5?%), and the median progression-free and overall survival times were 4.5?months (95?% CI: 3.5–5.0) and 15.0?months (95?% CI: 9.5–20.6) months, respectively. Toxicity was generally mild. Grade 3 or higher toxicity included neutropenia in 17.9?% of the patients, thrombocytopenia in 5.1?% and nausea in 7.7?%.

Conclusion

Combination chemotherapy with S-1 and irinotecan was considered an effective salvage regimen in patients with advanced or metastatic NSCLC.     

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.     

Phase II study of FOLFIRI regimen in patients with advanced colorectal cancer refractory to fluoropyrimidine and oxaliplatin

Purpose

To evaluate the efficacy and safety of FOLFIRI regimen in patients with advanced colorectal cancer refractory to fluoropyrimidine and oxaliplatin.

Methods

The FOLFIRI regimen consisted of intravenous infusion of irinotecan 180?mg/m² on day 1 plus leucovorin (LV) 400?mg/m² on day 1 plus 5-fluorouracil (5-FU) 400?mg/m² bolus on day 1 plus 46-hour intravenous infusion of 5-FU 2,400?mg/m², every 2?weeks as one cycle. The main selection criterion for this study was the advanced colorectal cancer refractory to fluoropyrimidine and oxaliplatin.

Results

Of the 57 evaluable patients for efficacy, 4 (7.5%) had a partial response, 36 (67.9%) had stable disease, and 13 (24.5%) had progressive disease. Median progression-free survival was 4.8?months (95% CI 3.9?C5.7?months), and median overall survival was 7.8?months (95% CI 13.1?C16.5?months). Safety analysis was based on the data of 57 evaluable patients. The most frequently observed grade 3 or 4 toxicities were neutropenia 16 (27.8%), nausea/vomiting 7 (12.3%), and diarrhea 1 (1.8%).

Conclusion

FOLFIRI regimen is effective and well tolerated in patients with advanced colorectal cancer refractory to fluoropyrimidine and oxaliplatin in Chinese population.     

Randomized phase II study of gemcitabine and S-1 combination versus gemcitabine alone in the treatment of unresectable advanced pancreatic cancer (Japan Clinical Cancer Research Organization PC-01 study)

Purpose

To evaluate the efficacy and safety of the combination of gemcitabine (GEM) and S-1 (GS) in comparison to GEM alone (G) for unresectable pancreatic cancer.

Methods

In this multicenter randomized phase II study, we randomly assigned unresectable pancreatic cancer patients to either the GS group or the G group. The GS group regimen consists of intravenous 1,000?mg/m² GEM during 30?min on days 1 and 8, combined with 80?mg/m² oral S-1 twice daily on days 1–14, repeated every 3?weeks. On the other hand, the G group regimen consists of intravenous 1,000?mg/m² GEM on days 1, 8, and 15, repeated every 4?weeks. The primary endpoint was objective response rate (ORR). Secondary end points included treatment toxicity, clinical response benefit, progression-free survival (PFS), and overall survival.

Results

We registered 117 patients from 16 institutions between June 2007 and August, 2010. The ORR of the GS group was 28.3%, whereas that of the G group was 6.8%. This difference was statistically significant (P?=?0.005). The disease control rate was 64.2% in the GS group and 44.1% in the G group. Median PFS was 6.15?months in the GS group and 3.78?month in the G group. This was also statistically significant (P?=?0.0007). Moreover, the median overall survival (OS) of the GS group was significantly longer than that of the G group (13.7?months vs. 8.0?months; P?=?0.035). The major grade 3–4 adverse events were neutropenia (54.7% in the GS group and 22.0% in the G group), thrombocytopenia (15.1% in the GS group and 5.1% in the G group), and skin rash (9.4% in the GS group).

Conclusions

The GS group showed stronger anticancer activity than the G group, suggesting the need for a large randomized phase III study to confirm GS advantages in a specific subset.     

Erythropoietin treatment in chemotherapy-induced anemia in previously untreated advanced esophagogastric cancer patients

Background

The impact of erythropoiesis-stimulating agents in chemotherapy-induced anemia has been a constant topic of debate over recent years. We prospectively assessed the efficacy of epoetin beta (Epo-b) in improving hemoglobin (Hb) levels and outcome in patients within an open label, randomized clinical phase II trial with advanced or metastatic gastric/esophagogastric cancer.

Methods

Previously untreated patients were randomized to receive 3-weekly cycles of capecitabine (1000 mg/m² bid) for 14 days plus on day 1 either irinotecan 250 mg/m² or cisplatin 80 mg/m². Epo-b (30000 IU once weekly) was initiated in patients with Hb <11 g/dl and continued until Hb ≥12 g/dl was reached. If after 4 weeks the Hb increase was <0.5 g/dl, Epo-b was increased to 30000 IU, twice weekly.

Results

Of 118 patients enrolled, 32 received Epo-b treatment; of these, 65 % achieved an increase in Hb levels of at least 2 g/dl, with 74 % achieving the target Hb of ≥12 g/dl. Within the study population, patients receiving Epo-b showed better overall survival (median 14.5 vs. 8.0 months, P = 0.056) as well as a significantly improved disease control rate (78 vs. 55 %, P = 0.025). Patients in the irinotecan group profited significantly (P < 0.05) in terms of progression-free survival and overall survival under Epo-b treatment (median 6.5 vs 4.1 months and median 15.4 vs 8.4 months, respectively).

Conclusions

Epo-b was effective in raising Hb levels in patients with advanced esophagogastric cancer. Patients receiving Epo-b had a significantly increased response to chemotherapy and a clear trend to improved survival.     

Phase II trial of induction irinotecan-cisplatin followed by concurrent irinotecan-cisplatin and radiotherapy for unresectable, locally advanced gastric and oesophageal-gastric junction adenocarcinoma

Purpose

The prognosis of patients with unresectable M0 gastric cancer remains very poor. We performed a phase II trial to explore the efficacy and toxicity of induction irinotecan-cisplatin (IC) followed by concurrent irinotecan-cisplatin and radiotherapy (IC/RT) in this setting.

Methods and materials

Patients with unresectable M0 gastric (GC) or oesophageal-gastric junction (EGJC) adenocarcinomas were treated with two courses of IC (irinotecan, 65?mg/m²; cisplatin, 30?mg/m² on days 1 and 8 every 21?days) followed by IC/RT (daily radiotherapy??45?Gy??with concurrent IC: irinotecan, 65?mg/m², and cisplatin, 30?mg/m², on days 1, 8, 15, and 22). Resectability was reassessed after this treatment, and surgical resection was performed if feasible. The primary endpoint was the R0 resection rate after induction treatment.

Results

Seventeen patients were included in the study (EGJC: 6; GC: 11). An R0 resection was achieved in only 5 patients (29%), and according to the design of the trial (Simon??s optimal two-stage) accrual of patients was terminated after the first stage. No patient died during IC, whereas 3 patients (24%) died during IC/RT and one of 5 resected patients (20%) died during the first 30?days after resection. The median survival was 10.5?months, and the actuarial 2-year survival rate was 27%.

Conclusions

Induction IC followed by IC/RT showed poor efficacy and significant toxicity in patients with unresectable GC/EGJC.     

Bevacizumab plus gemcitabine and oxaliplatin as first-line therapy for metastatic or locally advanced pancreatic cancer: a phase II trial

Purpose

The gemcitabine and oxaliplatin (GEMOX) has yielded among the longest progression-free survival durations in patients with advanced pancreatic cancer (APC). We postulated that adding bevacizumab would increase the effectiveness of GEMOX.

Methods

Eligible patients had stage III or IV pancreatic cancer, ECOG PS 0-2, and no prior gemcitabine. Treatment included 1,000?mg/m² intravenous gemcitabine over 100?min on day 1, 10?mg/kg intravenous bevacizumab on day 1, and 100?mg/m² oxaliplatin given on day 2. Cycles were repeated every 2?weeks. CT imaging was performed every 6?weeks.

Results

Fifty patients were enrolled: 14 had stage III disease, the remainder stage IV. Median age was 59?years. Fourty-five patients were ECOG 0-1. The grade 3?C4 toxicity rate was 94%; fatigue (47%) and nausea (40%) were frequent. One patient died after a bowel perforation; a second died of a CVA. The median PFS was 4.9?months; median survival was 11.9?months; 1?year survival was 42%. Locally advanced patients lived 12.8?months; metastatic patients lived 10.2?months. Patients developing grade 3 hypertension were more likely to have a radiologic response (P?=?.012); survival among the top and bottom quintiles of hypertension was 14.7 and 6.2?months, respectively. Survival correlated with baseline CA 19?C9 (P?=?.004) and radiologic response. The overall response rate was 36%; 34% demonstrated stable disease.

Conclusions

The GEMOX/bevacizumab regimen demonstrated an excellent median overall survival but did not meet our objective of a 14?month median survival. Toxicity was significant. We do not recommend further evaluation of this regimen.     

Preoperative Platelet Count Associates with Survival and Distant Metastasis in Surgically Resected Colorectal Cancer Patients

Objective

Platelets have been implicated in cancer metastasis and prognosis. No population-based study has been reported as to whether preoperative platelet count directly predicts metastatic recurrence of colorectal cancer (CRC) patients.

Design

Using a well-characterized cohort of 1,513 surgically resected CRC patients, we assessed the predictive roles of preoperative platelet count in overall survival, overall recurrence, as well as locoregional and distant metastatic recurrences.

Results

Patients with clinically high platelet count (≥400?×?10⁹/L) measured within 1 month before surgery had a significantly unfavorable survival (hazard ratio [HR]?=?1.66, 95 % confidence interval [CI] 1.34–2.05, P?=?2.6?×?10^?6, P _{log rank}?=?1.1?×?10^?11) and recurrence (HR?=?1.90, 1.24–2.93, P?=?0.003, P _{log rank}?=?0.003). The association of platelet count with recurrence was evident only in patients with metastatic (HR?=?2.81, 1.67–4.74, P?=?1.1?×?10^?4, P _{log rank}?=?2.6?×?10^?6) but not locoregional recurrence (HR?=?0.59, 95 % CI 0.21–1.68, P?=?0.325, P _{log rank}?=?0.152). The findings were internally validated through bootstrap resampling (P?<?0.01 at 98.6 % of resampling). Consistently, platelet count was significantly higher in deceased than living patients (P?<?0.0001) and in patients with metastatic recurrence than locoregional (P?=?0.004) or nonrecurrent patients (P?<?0.0001). Time-dependent modeling indicated that the increased risks for death and metastasis associated with elevated preoperative platelet counts persisted up to 5 years after surgery.

Conclusion

Our data demonstrated that clinically high level of preoperative platelets was an independent predictor of CRC survival and metastasis. As an important component of the routinely tested complete blood count panel, platelet count may be a cost-effective and noninvasive marker for CRC prognosis and a potential intervention target to prevent metastatic recurrence.     

Phase I study of intraperitoneal irinotecan in patients with gastric adenocarcinoma with peritoneal seeding

Purpose

The objectives of this phase I study were to determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLTs), and preliminary efficacy of intraperitoneally administered irinotecan (CPT-11) in gastric cancer patients with peritoneal seeding.

Experimental design

Gastric adenocarcinoma patients with surgical biopsy proven peritoneal seeding were enrolled at the time of surgery. Prior to IP chemotherapy, patients underwent palliative gastrectomy and CAPD catheter insertion in which CPT-11 was administered on postoperative day 1. The IP CPT-11 was initiated at 50?mg/m², which was escalated to 100, 150, 200, 250, and 300?mg/m². IP CPT-11 chemotherapy was repeated every 3?weeks.

Results

Seventeen patients received a total of 56?cycles at five different CPT-11 dose levels. The DLTs were neutropenic fever, neutropenia, and diarrhea. At the dose level 2 (100?mg/m²), there were one DLTs in one of the first cohort of three patients, but no DLTs at the second cohort of this level. At the dose level 5 (250?mg/m²), two DLTs were detected in the first two patients; thus, the accrual was stopped resulting in the recommended dose of IP CPT-11 of 200?mg/m². Median progression-free survival was 8.6?months (95% CI, 5.9,11.2), and median overall survival was 15.6?months (95% CI, 8.4,22.8). Pharmacokinetic results of the study showed that the C _max of peritoneal SN-38 was achieved earlier than that of plasma SN-38.

Conclusions

Intraperitoneally administered CPT-11 was feasible and tolerable. Further, phase II study of IP CPT-11 in gastric cancer patients with peritoneal seeding is warranted.     

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 randomized phase II study of PX-12, an inhibitor of thioredoxin in patients with advanced cancer of the pancreas following progression after a gemcitabine-containing combination

Purpose

This study evaluated PX-12, a novel small molecule inhibitor of the proto-oncogene (Trx-1), in patients with previously treated advanced pancreatic cancer (APC).

Methods

PX-12 (54 or 128?mg/m²) was administered by 3-hour IV infusion daily ×5?days every 21?days (n?=?17). Patients were randomized to either 54 or 128?mg/m² and then stratified based on CA 19-9 level (??1,000 vs. <1,000?U/ml) and SUV values on PET scans (??7.0 vs. <7.0). The primary endpoint was based on a progression-free survival (PFS) at 4?months in ??40% of patients, and required 40 patients in each arm. An amendment required elevated Trx-1 levels (>18?ng/ml) as an entry criteria after the first 17 patients were accrued.

Results

Plasma Trx-1 levels were elevated in 3/28 (11%) patients screened for study. The grade of the expired metabolite odor was higher in the 128?mg/m² arm. Therapy was well tolerated, and Grade ??3 adverse events were uncommon. The best response was stable disease in 2 patients. There was no consistent decrease in SUV, Trx-1 levels or CA 19-9 levels with therapy. No patients had a PFS of >4?months. Median PFS and survival were 0.9?months (95% CI 0.5?C1.2) and 3.2?months (95% CI 2.4?C4.2), respectively.

Conclusions

Due to the lack of significant antitumor activity and unexpectedly low baseline Trx-1 levels, the study was terminated early. PX-12 does not appear to be active in unselected patients with previously treated APC.     

Comparative analysis of the efficacy and safety of chemotherapy with oxaliplatin plus fluorouracil/leucovorin between elderly patients over 65?years and younger patients with advanced gastric cancer

Background

A chemotherapy regimen with oxaliplatin, fluorouracil, and leucovorin is commonly used to treat advanced gastric cancer (AGC). This study was designed to compare the efficacy and the safety of oxaliplatin plus fluorouracil/leucovorin administered biweekly (mFOLFOX6) between elderly patients aged over 65?years and younger counterparts with AGC.

Methods

This analysis included 82 AGC patients (≥65:31, <65:51). Patients with previously untreated chemo-na?ve advanced adenocarcinoma of the stomach received oxaliplatin 85?mg/m², 5-FU bolus 400?mg/m² on day?1 and 5-FU 1,500?mg/m², leucovorin 75?mg/m² 22?h infusion on days?1 and 2 every 2?weeks. The aim of the study was to compare efficacy and safety, including response rate (RR), progression-free survival (PFS), overall survival, and grade ≥3 adverse events, between patients aged ≥65 years and patients aged <65 years.

Results

Median progression-free survival (PFS) was not significantly different between both groups (≥65: 5.8?months, <65: 5.7?months, respectively, HR 0.77, 95% CI: 0.44–1.16, P?=?0.18). Median overall survival was not significantly different between both groups (≥65: 10.3?months, <65: 9.5?months HR 0.83, 95% CI: 0.50–1.37, P?=?0.46). The rate of grade 3 or 4 neutropenia did not differ with age group (≥65: 51.6%, <65: 43.1%); nor did the rates of neutropenic fever (≥65: 16.1%, <65: 5.9%), and infection without neutropenia (≥65: 3.2%, <65: 3.9%). Rates of grade ≥3 toxicities such as thrombocytopenia, nausea/vomiting, or peripheral neuropathy were not significantly different between the two groups.

Conclusions

mFOLFOX6 maintains its efficacy and safety in elderly patients aged over 65?years in comparison with AGC patients aged <65 years. Its judicious use should be considered regardless of age.     

Phase I trial of irinotecan and amrubicin with granulocyte colony-stimulating factor support in extensive-stage small-cell lung cancer

Purpose

We conducted a phase I trial of irinotecan (CPT-11), a topoisomerase I inhibitor, combined with amrubicin, a topoisomerase II inhibitor, with recombinant human granulocyte colony-stimulating factor (rhG-CSF) support to overcome the neutropenia associated with this particular combination. The aim was to determine the maximum tolerated dose (MTD) of amrubicin combined with a fixed dose of CPT-11 and the dose-limiting toxicities (DLTs) of this combination in extensive-stage small-cell lung cancer (ED-SCLC) patients.

Methods

Fifteen patients with ED-SCLC were treated at 3-week intervals with amrubicin on days 1–3 plus 60?mg/m² CPT-11 on days 1 and 8. In addition, prophylactic rhG-CSF (50?μg/m²) was given from day 4 to day 21, except on the day of CPT-11 administration. Amrubicin was started at 30?mg/m² and then escalated in 5?mg/m² increments until MTD was reached.

Results

The MTD of amrubicin was 35?mg/m², since 2 of 4 patients experienced DLTs during the first cycle of treatment at the 40 mg/m² dose level. Neutropenia, neutropenic fever, ileus, and diarrhea were the DLTs. There were 13 partial responses among the 13 assessable patients, yielding an overall response rate of 100?%. Median progression-free survival and overall survival were 7.4?months and 13.4?months, respectively.

Conclusion

The combination of amrubicin and CPT-11 showed high activity against ED-SCLC with acceptable toxicity. Use of rhG-CSF allowed the dose of amrubicin to be raised 40?% above that in the original regimen (60?mg/m² CPT-11 and 25?mg/m² amrubicin).     

Prognostic factors in patients with advanced biliary tract cancer receiving chemotherapy

Purpose

Prognostic factors for patients with advanced biliary tract cancer receiving chemotherapy are presently not well established. Gallbladder cancer and intra-hepatic cholangiocarcinoma are previously reported prognostic factors of poor prognosis; however, tumor volume has not been analyzed in these previous reports.

Methods

We analyzed 56 consecutive patients with advanced biliary tract cancer who had received gemcitabine and S-1 combination chemotherapy as first-line palliative chemotherapy. Prognostic factors, including the baseline sum longest diameter (BSLD) representing tumor volume in Response Evaluation Criteria in Solid Tumor, were evaluated.

Results

By multivariate analysis, age ??70 (HR 3.01, 95% CI 1.25?C7.31, P?=?0.014) and larger BSLD (HR 1.09, 95% CI 1.01?C1.18, P?=?0.021) were statistically significant independent predictors of poor prognosis. Primary biliary site was not identified as a prognostic factor (P?=?0.728). Median survival times of patients with BSLDs????9.0?cm and BSLDs?>?9.0?cm were 18.7 and 8.8?months, respectively (P?=?0.024).

Conclusions

Age and BSLD were identified as strong prognostic factors for patients with advanced biliary tract cancer receiving chemotherapy. Tumor volume might be more important than primary biliary site for the prognosis of advanced biliary tract cancer.     

Second-line chemotherapy for advanced or recurrent endometrial carcinoma previously treated with paclitaxel and carboplatin, with or without epirubicin

Purpose

A combined chemotherapy of taxane and platinum, with or without anthracycline, has been used as a standard first-line regimen. The purpose of this study was to investigate the effectiveness of second-line chemotherapy for treatment of advanced or recurrent endometrial carcinoma previously treated with a combined chemotherapy of taxane and platinum, with or without anthracycline.

Methods

During the 2000?C2008 study period, 723 patients were diagnosed with endometrial cancer at the Departments of Obstetrics and Gynecology of the Osaka University and the Osaka Rosai Hospitals, Osaka, Japan. The subset of these cases that eventually required treatment by second-line chemotherapy was retrospectively analyzed.

Results

Response rate to second-line chemotherapy was 25%. Treatment-free interval (TFI) of ???or?<6?months was demonstrated to be significantly associated with the response to second-line chemotherapy (P?=?0.0026), progression-free survival (P?=?0.0003) and overall survival (P?=?0.025). The second-line chemotherapy similar to the first-line regimen was ineffective in all the 7 cases (100%) whose TFI was shorter than 6?months. Multivariate analysis showed that TFI was the most significantly important factor predicting the effectiveness of second-line chemotherapy (the adjusted hazard ratio of TFI on PFS and OS: 3.482, 95% CI, 1.641?C7.388, P?=?0.0012, and 2.341, 95% CI, 1.034?C5.301, P?=?0.042, respectively).

Conclusions

Our present study provides, for the first time, evidence that the majority of refractory or recurrent diseases, if they occur within 6?months of a first-line chemotherapy using taxane and platinum with or without anthracycline, are non-responsive to the current regimens of second-line chemotherapy.     

Paclitaxel as second-line chemotherapy in patients with gemcitabine-refractory pancreatic cancer: a retrospective study

Background

We evaluated the efficacy and feasibility of paclitaxel in patients with gemcitabine-refractory pancreatic cancer. We also evaluated the correlation between tumor marker decline and response rate.

Methods

Thirty patients histologically diagnosed with pancreatic cancer who had undergone paclitaxel treatment as salvage chemotherapy were retrospectively analyzed. Paclitaxel treatment was performed with 80?mg/(m²?week) for 3?weeks followed by 1?week rest, and this was continued until failure. Tumor marker response was evaluated by measuring levels of carbohydrate antigen 19-9, carcinoembryonic antigen, and DUPAN-2 monthly.

Results

In total, 272?weekly paclitaxel treatments were performed. The median number of treatments per patient was 8 (range 1??2). The median overall survival from the start of paclitaxel treatment was 6.7?months (range 1.2??8.8). The response rate was 10% (3/30 patients) and the disease control rate was 46.7% (14/30 patients). Although grade 3 and 4 hematological and non-hematological toxicities were seen in 7 and 6 patients, respectively, adverse events were managed by conservative treatment. We found a significant correlation between the disease control rate and tumor marker decline within 2?months of paclitaxel treatment (P?=?0.01). Patients with tumor marker decline tended to survive longer.

Conclusion

Weekly administration of paclitaxel in patients with gemcitabine-refractory pancreatic cancer seems to be well tolerated and can be effective. Paclitaxel treatment should be considered as salvage chemotherapy after gemcitabine failure in patients with good performance status.     

A randomized phase II study of biweekly irinotecan monotherapy or a combination of irinotecan plus 5-fluorouracil/leucovorin (mFOLFIRI) in patients with metastatic gastric adenocarcinoma refractory to or progressive after first-line chemotherapy

Background

The aim of this study was to evaluate the efficacy of irinotecan (CPT-11) monotherapy and CPT-11 plus 5-fluorouracil (5-FU)/leucovorin (LV) combination (mFOLFIRI) as second-line treatment in patients with advanced gastric cancer (AGC).

Methods

A total of 59 patients were randomly assigned to either CPT-11 (150 mg/m² iv on day 1) or mFOLFIRI (CPT-11 150 mg/m² plus LV 20 mg/m² on day 1 followed by 5-FU 2,000 mg/m² over 48 h), every 2 weeks. The primary end point was objective response rate (ORR).

Results

Following random assignment, 29 patients received CPT-11 and 30 patients mFOLFIRI. The ORR was 17.2 % [95 % confidence interval (CI) 3.4–30.9] and 20.0 % (95 % CI 5.6–34.3) for the CPT-11 and mFOLFIRI arms, respectively (P = 0.525). There was no significant difference in median progression-free survival: 2.2 months (95 % CI 0.2–4.3) for CPT-11 versus 3.0 months (95 % CI 2.0–3.7) for mFOLFIRI (P = 0.481) or in median overall survival: 5.8 months (95 % CI 3.0–8.7), compared with 6.7 months (95 % CI 5.3–8.2) (P = 0.514). Grade 3/4 toxicity was observed in 21 and 28 events in the CPT-11 and mFOLFIRI arms, respectively.

Conclusions

Although this study had a small sample size and limited statistical power, CPT-11 monotherapy and mFOLFIRI appear to be equally active and tolerable as second-line chemotherapy for AGC. The addition of 5-FU/LV to CPT-11 did not significantly improve efficacy.     

Phase I and pharmacokinetic study of IHL-305 (PEGylated liposomal irinotecan) in patients with advanced solid tumors

Purpose

IHL-305 is a novel PEGylated liposome containing irinotecan. This study examined the safety profile and pharmacokinetics of IHL-305 and established the maximum tolerated dose and recommended phase II dose (RP2D).

Patients and methods

In a standard 3?+?3 design, IHL-305 was administered IV on day 1 of a 28-day treatment schedule. Subsequently, a 14-day treatment schedule was also explored. Two patient populations were evaluated separately: Patients with at least one wild-type (wt) allele of UGT1A1 (UDP glucoronosyltransferase 1A1) wt/wt or wt/*28 as one group (referred to as UGT1A1 wt group) and patients with UGT1A1*28 homozygous variant (*28/*28) as another group.

Results

Sixty patients were treated: 42 on the 28-day schedule and 18 on the 14-day schedule. Seven patients were homozygous variant (*28/*28). In the UGT1A1 wt group, the MTD and RP2D of IHL-305 was 160?mg/m² every 28?days and 80?mg/m² every 14?days. DLTs included nausea, vomiting, diarrhea, and neutropenia. The most common adverse events were nausea (75?%), vomiting (52?%), diarrhea (62?%), anorexia (57?%), and fatigue (57?%). At the MTD for both schedules, IHL-305 administration resulted in a high and prolonged exposure of sum total irinotecan, released irinotecan, and SN-38 in plasma. One partial response was observed in a patient with breast cancer and eight patients had stable disease for >6?months.

Conclusions

IHL-305, a novel preparation of irinotecan encapsulated in liposomes, can be safely given to patients in a repeated fashion on a 4- or 2-week dosing schedule.