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).     

A phase I study of combination therapy with S-1 and irinotecan in patients with previously untreated metastatic or recurrent colorectal cancer

Background

To investigate the combination of S-1 and irinotecan (CPT-11) as an alternative to infusional 5-fluorouracil/leucovorin plus CPT-11, we performed a phase I trial to determine the maximum tolerated dose, recommended dose (RD), and dose-limiting toxicities (DLTs) in patients with metastatic or recurrent colorectal cancer.

Patients and methods

S-1 and CPT-11 doses were escalated using a standard 3?+?3 design. S-1 was administered orally at 70?mg/m² (levels 1?C3) or 80?mg/m² (levels 4 and 5) for 14 consecutive days followed by 1-week rest. CPT-11 was administered intravenously on day 1, at 175?mg/m² (level 1), 200?mg/m² (level 2), 225?mg/m² (levels 3 and 4), or 250?mg/m² (level 5). Treatment was repeated every 3?weeks, unless disease progression or severe toxicities were observed.

Results

Twenty-three patients were treated. One patient at each of levels 2 and 4 developed a DLT, grade 3 ileus, and grade 3 diarrhea, respectively. At both levels, an additional three patients did not experience DLTs. At level 5, two of five patients experienced DLTs, including grade 3 enteritis and grade 4 neutropenia for more than 5?days. The RD was determined at level 4 (80?mg/m² S-1 and 225?mg/m² CPT-11). An objective response was observed in 7 of 17 patients with measurable disease: 2 of 5 at level 2; 3 of 4 at level 4; and 2 of 4 at level 5.

Conclusions

The RDs of CPT-11 and S-1 were determined as 225 and 80?mg/m², respectively, and further phase II trials are warranted.     

Association of right-sided tumors with high thymidine phosphorylase gene expression levels and the response to oral uracil and tegafur/leucovorin chemotherapy among patients with colorectal cancer

Purpose

To identify useful predictive factors for the response to 5-fluorouracil (5-FU)/leucovorin (LV) and oral uracil and tegafur (UFT)/LV chemotherapy among patients with colorectal cancer, we investigated the association between the gene expression levels of pyrimidine and folate metabolism-related enzymes in colorectal cancer (CRC) tissues and the response to UFT/LV neoadjuvant chemotherapy.

Methods

The subjects were 76 CRC patients who were scheduled to undergo surgery. UFT (300?mg/m²/day) and LV (75?mg/body/day) were administered for 2 weeks before surgery. Biopsy samples were endoscopically obtained before drug administration. The gene expression levels of 14 genes in the biopsy samples were quantitatively evaluated using a real-time polymerase chain reaction (RT-PCR) assay.

Results

Fifteen patients (19.7?%) with marked pathological regression were judged to be responders. Thymidine phosphorylase (TP) gene expression levels among the responders were significantly higher than those among the non-responders. Right-sided tumors with high TP gene expression levels were associated with a significantly higher response rate to UFT/LV chemotherapy than left-sided tumors.

Conclusions

TP gene expression levels in primary CRC tissues and the primary tumor site may be useful predictors of the efficacy of oral UFT/LV chemotherapy.     

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 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.     

A phase I study of irinotecan and pegylated liposomal doxorubicin in recurrent ovarian cancer (Tohoku Gynecologic Cancer Unit 104 study)

Purpose

A phase I clinical study was conducted to determine the maximum tolerated dose (MTD) and the recommended dose (RD) of irinotecan hydrochloride (CPT-11) in CPT-11/pegylated liposomal doxorubicin (PLD) combination therapy, a novel treatment regimen for platinum- and taxane-resistant recurrent ovarian cancer.

Methods

Pegylated liposomal doxorubicin was administered intravenously on day 3 at a fixed dose of 30 mg/m². CPT-11 was administered intravenously on days 1 and 15, at a dose of 50 mg/m² on both days. One course of chemotherapy was 28 days, and patients were given a maximum of six courses, with the CPT-11 dose being increased in increments of 10 mg/m² (level 1, 50 mg/m²; level 2, 60 mg/m²; level 3, 70 mg/m²; level 4, 80 mg/m²) to determine MTD and RD.

Results

During the period from April 2010 to March 2013, three patients were enrolled for each level. In the first course, no dose-limiting toxicity occurred in any of the patients. Grade 4 neutropenia was observed in two of three patients at level 4. At level 4, the antitumor effect was a partial response (PR) in two of the three patients and stable disease (SD) in one. At level 3, one of the three patients showed PR and two had SD. At level 4, the start of the next course was postponed in two of three patients. In addition, one patient at level 4 experienced hemotoxicity that met the criteria for dose reduction in the next course. The above results suggested that administration of CPT-11 at dose level 5 (90 mg/m²) would result in more patients with severe neutropenia and in more patients requiring postponement of the next course or a dose reduction. Based on the above, the RD of CPT-11 was determined to be 80 mg/m².

Conclusions

The results suggest that CPT-11/PLD combination therapy for recurrent ovarian cancer is a useful treatment method with a high response rate and manageable adverse reactions. In the future phase II study, the safety and efficacy of this therapy will be assessed at 80 mg/m² of CPT-11 and 30 mg/m² of PLD.     

Area under the curve calculation of nedaplatin dose used in combination chemotherapy with irinotecan in a phase I study of gynecologic malignancies

Purpose

Although the pharmacokinetic mechanism of nedaplatin (NDP) is similar to carboplatin, the dose of NDP is typically determined by body surface area and not by the area under the curve (AUC). We conducted a phase I study to determine the AUC-calculated optimal dosage of NDP used in combination chemotherapy with irinotecan (CPT-11) for gynecologic malignancies.

Methods

A total of 15 patients who were to undergo combination chemotherapy consisting of NDP and CPT-11 were enrolled in this study. The dose of CPT-11 was administered at a fixed dose of 60?mg/m² and that of NDP was gradually increased from 8 to 12???g?h/mL (AUC). The individual dose of NDP was calculated based on cratinine clearance of the patient according following formula: Dose_NDP?=?AUC?×?CL_NDP, where CL_NDP?=?0.0738?×?creatinine clearance?+?4.47 (Ishibashi??s formula).

Results

One patient had dose-limiting toxicity (DLT) at level 1, and two patients suffered DLT at level 3. The dosage of NDP at AUC 12 was determined to be the maximum tolerated dose in combination chemotherapy with CPT-11, even though only two of the six patients showed DLT at level 3.

Conclusions

The recommended dosage of NDP calculated by AUC with Ishibashi??s fomula was set to AUC 10 in combination chemotherapy with CPT-11.     

A phase I trial of arterial infusion chemotherapy with gemcitabine and 5-fluorouracil for unresectable biliary tract cancer

Background

Many clinical trials have been conducted with gemcitabine- or 5-fluorouracil-based regimens as treatment for unresectable biliary tract cancer; however, the results remain unsatisfactory. Because further therapeutic improvements are required, we conducted a phase I study of arterial infusion chemotherapy using a combination of gemcitabine and 5-fluorouracil.

Methods

In the first 3 cohorts, patients were to receive an arterial infusion of gemcitabine 600, 800 or 1000?mg/m², respectively, over 30?min on days 1 and 15, plus a continuous arterial infusion of 5-fluorouracil 300?mg/m²/day on days 1–5 and 15–19. In the final cohort, patients were to receive an arterial infusion of gemcitabine 1000?mg/m² over 30?min on days 1 and 15, plus 5-fluorouracil 400?mg/m²/day on days 1–5 and 15–19.

Results

Eighteen patients were enrolled. In the final cohort, three of six patients experienced grade 3 non-hematological toxicities (cholecystitis, cellulitis and pneumonia). Thus, we determined the maximum tolerated doses of gemcitabine and 5-fluorouracil in arterial infusion chemotherapy to be 1000 and 400?mg/m², respectively.

Conclusion

This regimen of gemcitabine and 5-fluorouracil is tolerable and warrants further investigation in biliary tract cancer.     

CPT-11 as a second-line treatment for patients with advanced/metastatic gastric cancer who failed S-1 (CCOG0702)

Background

In Japan, CPT-11 is often used to treat unresectable gastric cancer in the second-line setting. However, evidence regarding benefit of second-line chemotherapy remains sparse, especially after failing S-1.

Methods

A phase II study to evaluate the efficacy and safety of weekly administration of CPT-11 at a dose of 100 mg/m² after failing a S-1-containing first-line treatment was planned with response rate as a primary end point. UGT1A1*6, *27, and *28 genotyping were performed in all cases, and those found to have either homozygous for *28, homozygous for *6, heterozygous for both *6 and *28, and heterozygous for *27 were rendered ineligible for the phase II trial.

Results

Two patients of homozygous for *28, two patients of homozygous for *6, and one patient of heterozygous for *27 were found among 39 recruited patients. The median number of courses delivered was 3 courses. The overall response rate was 15.4 % and disease control rate was 65.4 %. The median time to treatment failure was 87.5 days and median overall survival was 268 days. Twenty-two (73 %) of 30 valuable patients experienced protocol-specified skip of treatment and 8 (30 %) of patients could continue treatment with dose reduction. ≥G3 neutropenia was found in 30 % and ≥G3 anorexia and diarrhea were found in 23 and 17 %, respectively.

Conclusion

Weekly CPT-11 at 100 mg/m² showed moderate response among gastric cancer patients who were refractory to S-1, but the disease control rate seemed meaningful. Even after selection of patients by UGT1A1 polymorphism of *6, *27, and *28, severe toxic events could not be prevented completely.     

A phase II study of biweekly mitomycin C and irinotecan combination therapy in patients with fluoropyrimidine-resistant advanced gastric cancer: a report from the Gastrointestinal Oncology Group of the Japan Clinical Oncology Group (JCOG0109-DI Trial)

Background

Preclinical studies have shown that mitomycin C (MMC) acts synergistically with irinotecan (CPT-11). In this phase II study, we evaluated the efficacy and toxicity of MMC/CPT-11 therapy as second-line chemotherapy for patients with fluoropyrimidine-resistant advanced gastric cancer.

Methods

Eligible patients had evidence of tumor progression despite prior treatment with fluoropyrimidine-based regimens or had relapsed within 6?months after completion of therapy with adjuvant fluoropyrimidines. Treatment consisted of MMC (5?mg/m²) and CPT-11 (150?mg/m²) administered i.v. every 2?weeks. The primary endpoint was the response rate (RR). Our hypothesis was that this combination therapy was efficacious when the lower boundary of the 95% confidence interval (CI) of the RR exceeded 20% of the threshold RR.

Results

Between April 2002 and July 2003, 45 eligible patients were registered and analyzed. Among the 45 patients, 40 (89%) had previously received chemotherapy for metastasis and 24 (53%) had a performance status (PS) of 0. Thirteen partial responses were obtained among the 45 patients, resulting in an overall RR of 29% (95% CI, 16?C42%). The median time to progression was 4.1?months, and the median survival time was 10?months, with a 1-year survival rate of 36%. Grade 4 neutropenia was observed in 29% of the patients, whereas febrile neutropenia occurred in 9%. The incidence rates of grade 3 nausea and diarrhea were 13 and 2%, respectively.

Conclusions

Although this study did not achieve the per-protocol definition of activity, the progression-free survival and overall survival appeared to be promising, with acceptable tolerability. Thus, MMC/CPT-11 therapy as second-line chemotherapy for fluoropyrimidine-resistant advanced gastric cancer presents a potential treatment option in patients with a good PS.     

A phase I study of S-1 and irinotecan combination therapy in previously treated advanced non-small cell lung cancer patients

Background

This phase I study was conducted to evaluate the feasibility and to determine the recommended doses of the combination therapy of S-1 and irinotecan (CPT-11) in patients with advanced non-small cell lung cancer (NSCLC) as second-line treatment.

Methods

Patients with NSCLC who were previously treated with one chemotherapy regimen and had a performance status of 0 or 1 were eligible. CPT-11 was administered at 60 mg/m² (level 1), 80 mg/m² (level 2) on days 1 and 8, and oral S-1 was administered at 80 mg/day for body surface area (BSA) less than 1.25 m², 100 mg/day for BSA 1.25–1.5 m², and 120 mg/day for BSA more than 1.5 m² on days 1–14 every 3 weeks. The dose-limiting toxicity (DLT) was defined as grade 4 leukocytopenia or neutropenia, grade ≥3 neutropenia with fever over 38°C, grade ≥3 thrombocytopenia, or grade ≥3 major nonhematological toxicities.

Results

Nine patients were enrolled in the study. None of 3 patients enrolled in level 1 had any DLT. Of 6 patients in level 2, 2 patients had grade 3 diarrhea and one had grade 3 interstitial pneumonia. Level 1 was declared as the recommended dose.

Conclusion

The feasibility of the combination therapy of S-1 and CPT-11 was shown in the second-line setting for the treatment of advanced NSCLC. The recommended dose of CPT-11 was 60 mg/m² combined with standard dose of S-1 for phase II trials of pretreated advanced NSCLC patients.     

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.     

Efficacy and toxicity of concurrent chemoradiotherapy in patients with advanced oropharyngeal squamous cell carcinoma

Purpose

The aim of this study was to evaluate the feasibility and toxicity of concurrent chemoradiotherapy (CCRT) with docetaxel, cisplatin (CDDP) and 5-fluorouracil (5-FU) (TPF regimen) or with CDDP, 5-FU, methotrexate and leucovorin (PFML regimen) in previously untreated patients with advanced oropharyngeal squamous cell carcinoma (SCC).

Methods

Fifty-six eligible patients with stage III or IV oropharyngeal SCC were treated with CCRT. Forty-four patients were men and 12 were women, and the average age of the patients was 58.8?years (range, 37?C72?years). In the TPF group, patients received CCRT with the TPF regimen [docetaxel (50?mg/m², day 1), CDDP (60?mg/m², day 4) and a continuous 5-FU infusion (600?mg/m²/day, days 1?C5)]. In the PFML group, patients received CCRT with the PFML regimen [CDDP (60?mg/m², day 4), a continuous 5-FU infusion (600?mg/m²/day, days 1?C5), methotrexate (30?mg/m², day 1) and leucovorin (10?mg/m²/day, days 1?C5)]. The total radiation dose was between 66.6 and 70.2?Gy.

Results

The overall 5-year survival rate was 64.6% in all patients, 68.6% in the resectable group and 47.4% in the unresectable group. The 5-year disease-specific survival rate was 72.2% in all patients, 78.1% in the resectable group and 47.7% in the unresectable group. Regarding clinical stage, the 5-year disease-specific survival rates were 91% in stage III, 72% in stage IVa and 44% in stage IVb.

Conclusion

CCRT with TPF or PFML regimen for advanced oropharyngeal SCC is tolerable and effective, especially in patients with resectable disease.     

Prospective multicenter study to investigate the introduction rate of second-line S-1 in gemcitabine-refractory unresectable pancreatic cancer

Purpose

S-1 is one of the second-line candidate agents for gemcitabine-refractory unresectable pancreatic cancer. Two phase II studies have been reported for second-line chemotherapy with S-1, but these studies did not investigate introduction rate and suitable dose of second-line S-1. Therefore, we conducted a prospective multicenter study in which chemo-na?ve patients were enrolled and had two levels of S-1 dose.

Methods

Chemo-na?ve patients with unresectable pancreatic cancer were enrolled. This study started with 80?mg/m²/day dose of S-1 as second-line chemotherapy and tolerability was checked. When tolerability was not confirmed in initial patients, the dose of S-1 was shifted to 60?mg/m²/day. When tolerability was confirmed at 80 or 60?mg/m²/day, the study continued, and up to 20 patients were accumulated with the dose. In addition, the introduction rate of second-line S-1 was examined.

Results

Six of the initial 7 patients with 80?mg/m²/day dose of S-1 completed one course of second-line chemotherapy. Twenty patients were accumulated with an 80?mg/m²/day dose of S-1. With the exception of one patient continued gemcitabine chemotherapy, two of the remaining 19 patients withdrew from this study because of toxicity during the period of gemcitabine chemotherapy. Fifteen of the remaining 17 gemcitabine-refractory patients could complete one course of S-1 as second-line chemotherapy with acceptable toxicity.

Conclusions

This prospective multicenter study showed that 15 (78.9%) out of 19 chemo-na?ve unresectable pancreatic cancer patients could complete one course of 80?mg/m²/day dose of S-1 as second-line chemotherapy after first-line gemcitabine chemotherapy failure with tolerable toxicity.     

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.     

A multicenter phase II study of combined chemotherapy with docetaxel, cisplatin, and S-1 in patients with unresectable or recurrent gastric cancer (KDOG 0601)

Purpose

We conducted a phase II study to evaluate the efficacy and safety of a triplet regimen of docetaxel, cisplatin, and S-1 in patients with unresectable or recurrent gastric cancer.

Methods

Docetaxel (40?mg/m²) and cisplatin (70 or 60?mg/m²) were given on day 1 of a 28-day cycle. S-1 (40?mg/m²) was given twice daily on days 1?C14. Treatment with this regimen was continued for a maximum of 6 cycles. Subsequently, patients with no disease progression received a combination of docetaxel and S-1.

Results

Fifty-nine patients were enrolled. The median number of administered cycles was 8 (range, 1?C25). Because some patients had serious myelosuppression and renal dysfunction with 70?mg/m² of cisplatin, dose of cisplatin was reduced to 60?mg/m² after 19 patients had been treated. Common severe toxic effects of grade 3 or 4 were leukocytopenia (44%), neutropenia (72%), anemia (15%), and febrile neutropenia (14%). The overall response rate of this group was 81% (95% confidence interval (CI), 71?C91%). The median overall survival and progression-free survival were 18.5 (95% CI, 15.6?C21.5) and 8.7 (95% CI, 6.7?C10.7) months, respectively.

Conclusions

Triplet of docetaxel, cisplatin, and S-1 is a well-tolerated and highly active regimen for advanced or recurrent gastric cancer. A 60?mg/m² of cisplatin is as effective as 70?mg/m² of cisplatin.     

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.     

Final results of randomized trials by the National Surgical Adjuvant Study of Colorectal Cancer (NSAS-CC)

Objective

In the latter 1990s, adjuvant chemotherapy for completely resected Stage III colorectal cancer remained controversial in Japan. We conducted two independent randomized controlled trials in patients with Stage III colon and rectal cancer.

Methods

Patients were randomly assigned to receive surgery alone or surgery followed by treatment with UFT (400?mg/m²/day), given for five consecutive days per week for 1?year. The primary endpoint was relapse-free survival (RFS), and the secondary endpoint was overall survival (OS).

Results

A total of 334 patients with colon cancer and 276 with rectal cancer were enrolled. The patients?? characteristics were similar between the UFT group and the Surgery-alone group. There was no significant difference in RFS or OS in colon cancer. In rectal cancer, however, RFS and OS were significantly better in the UFT group than in the Surgery-alone group. The only grade 4 toxicity in the UFT group was diarrhea, occurring in one patient with colon cancer and one patient with rectal cancer.

Conclusions

Postoperative adjuvant chemotherapy with UFT is successfully tolerated and improves RFS and OS in patients with Stage III rectal cancer. In colon cancer, the expected benefits were not obtained (hazard ratio?=?0.89).     

Biweekly vinorelbine and tegafur/uracil in patients with metastatic breast cancer previously treated with anthracyclines and taxanes: GEICAM 2000–02 phase II study

Introduction

To assess the efficacy and safety profile of biweekly vinorelbine and tegafur/uracil (UFT) as treatment in patients with metastatic breast cancer previously treated with anthracyclines and taxanes.

Patients and methods

Patients with histologically confirmed breast cancer, measurable disease, no more than one prior chemotherapy regimen for metastatic disease, an Eastern Cooperative Oncology Group (ECOG) performance status ≤2, and adequate bone marrow, renal and liver function were eligible. Patients received vinorelbine (30 mg/m² on day 1) and UFT (250 mg/m² daily) every two weeks for 12 cycles unless progression or unacceptable toxicity was observed.

Results

Thirty-seven patients were included and received 311 cycles of chemotherapy. Efficacy and toxicity analyses were carried out on an intention-to-treat basis. The overall response rate was 35% (95% CI: 20–53). With a median follow-up of 18.6 months (95% CI: 1.0–74.3), the median time to progression was 7.0 months (96% CI: 5.2–8.9) and the median overall survival was 19.4 months (95% CI: 11.1–27.8). The most common severe toxicities were neutropenia (38% of patients) and asthenia (11% of patients).

Conclusion

The combination of biweekly vinorelbine and UFT in patients with metastatic breast cancer pretreated with anthracyclines and taxanes is a well tolerated and effective regimen. AEMPS Trial Registration No.: 00-0534.     

Outcomes of a Phase I/II Trial of Hepatic Arterial Infusion of Oxaliplatin Combined with Intravenous 5-Fluorouracil and l-Leucovorin in Patients with Unresectable Liver Metastases from Colorectal Cancer After Systemic Chemotherapy Failure

Purpose

The purpose of this study was to assess hepatic arterial infusion (HAI) of oxaliplatin combined with intravenous 5-fluorouracil (5-FU) and l-leucovorin (l-LV) in colorectal cancer (CRC) patients with systemic chemotherapy failure in a phase I/II trial.

Methods

CRC patients with unresectable liver metastases following standard systemic chemotherapy failure were eligible. A catheter-port system for HAI was placed using interventional radiology. In phase I, escalating doses of oxaliplatin for levels 1 and 2 were set at 50 and 100 mg/m², respectively, and were combined with fixed doses of intravenous 5-FU (200 mg/m² bolus and 2400 mg/m²/46-h continuous infusion) and l-LV (200 mg/m²). The dose-limiting toxicity (DLT) was assessed, and the recommended dose (RD) was estimated. In phase II, patients receiving RD were included to assess the 6-month survival rate (the expected rate 80%), overall survival time, tumor response, and toxicity.

Results

In phase I, none of the six enrolled patients exhibited DLT. RD for oxaliplatin by HAI was estimated as 100 mg/m². In phase II, seven additional patients were enrolled. In patients receiving RD (n?=?10), the disease control rates for total lesions and liver lesions were 30 and 70%, respectively. The 6-month survival rate and the overall survival time were 53.3% and 6.9 months, respectively. There were no adverse reactions equivalent to DLT in any of the patients.

Conclusions

The estimated RD for oxaliplatin by HAI in combination with intravenous 5-FU and l-LV was 100 mg/m². This combination therapy was feasible and safe, but the expected efficacy was not achieved.