Correlation of capecitabine-induced skin toxicity with treatment efficacy in patients with metastatic colorectal cancer: results from the German AIO KRK-0104 trial

Background:

The AIO KRK-0104 randomised phase II trial investigated the efficacy and safety of two capecitabine-based regimens: combination of capecitabine and irinotecan (CAPIRI) plus cetuximab (CAPIRI-C) and combination of capecitabine with oxaliplatin (CAPOX) plus cetuximab (CAPOX-C) in the first-line treatment of metastatic colorectal cancer (mCRC). Treatment-related skin toxicity (ST) was evaluated separately for capecitabine and cetuximab. The present analysis investigates the correlation of capecitabine-attributed ST (Cape-ST) and parameters of treatment efficacy.

Methods:

Patients with mCRC were randomised to cetuximab (400 mg m⁻², day 1, followed by 250 mg m⁻² weekly) plus CAPIRI (irinotecan 200 mg m⁻², day 1; capecitabine 800 mg m⁻², twice daily, days 1–14, every 3 weeks), or cetuximab plus CAPOX (oxaliplatin 130 mg m⁻², day 1; capecitabine 1000 mg m⁻², twice daily, days 1–14, every 3 weeks).

Results:

Of 185 recruited patients, 149 (CAPIRI-C, n=78; CAPOX-C, n=71) received study treatment beyond the first tumour assessment and were evaluable for efficacy. Capecitabine-attributed ST, predominantly hand–foot syndrome, was observed in 32.2% of patients. Capecitabine-attributed ST grade 1–3 was associated with a significantly higher disease control rate (DCR) (97.9 vs 86.1%, P=0.038) compared with grade 0 toxicity. Moreover, Cape-ST grade 1–3 related to a markedly longer progression-free survival (PFS) (9.9 vs 5.6 months, P<0.001) and overall survival (OS) (32.8 vs 22.4 months, P=0.008). Separate analyses of treatment arms indicated that the effect of Cape-ST on PFS remained significant for both arms, whereas the effect on OS remained apparent as a strong trend.

Conclusion:

This analysis supports the hypothesis that for the evaluated regimens, a correlation exists between Cape-ST and treatment efficacy regarding DCR, PFS, and OS.     

Bevacizumab in combination with biweekly capecitabine and irinotecan, as first-line treatment for patients with metastatic colorectal cancer

Background:

Combination of capecitabine and irinotecan (XELIRI regimen) is an active and well tolerated treatment for metastatic colorectal cancer (mCRC). The aim of this study was to evaluate the efficacy and safety of this regimen in combination with bevacizumab (BV), as first-line treatment for mCRC.

Patients and methods:

A total of 46 consecutive patients received a combination of BV (5 mg kg⁻¹, day 1), irinotecan (175 mg m⁻², day 1) and capecitabine (1000 mg m⁻² twice daily on day 2–8), every 2 weeks. Patients were treated until disease progression or unacceptable toxicity. The primary objective was to determine the progression-free survival (PFS) and safety profile.

Results:

The overall response rate (ORR) was 67.4%, with a disease control rate (ORR+stable disease) of 93.5%. Median PFS and overall survival (OS) were 12.3 months (95% confidence interval (CI): 6.5–18.1 months) and 23.7 months (95% CI: 16.7–30.6 months), respectively. The most frequent grade 3/4 treatment-related adverse events were asthenia (7%), diarrhoea (7%), nausea (9%) and vomiting (7%).

Conclusion:

Bevacizumab combined with biweekly XELIRI is a highly active first-line regimen for mCRC treatment, showing encouraging PFS, ORR and OS with a good tolerability.     

Docetaxel and capecitabine for advanced gastric cancer: investigating dose-dependent efficacy in two patient cohorts

Background:

No comparisons of different doses of docetaxel-capecitabine in patients with advanced gastric cancer have been performed.

Methods:

Patients with previously untreated metastatic/locally advanced gastro-oesophageal or gastric adenocarcinoma were enrolled in a prospective multicentre phase II trial. Two sequential cohorts received docetaxel 75 mg m⁻² (day 1) plus capecitabine 1000 mg m⁻² twice daily (days 1–14) (cohort I) or docetaxel 60 mg m⁻² (day 1) plus capecitabine 800 mg m⁻² twice daily (days 1–14) (cohort II) every 3 weeks. The primary end point was confirmed overall response rate.

Results:

In all, 91 patients were enrolled (cohort I, n=40; cohort II, n=51) and 87 were evaluable for efficacy (n=38, 49, respectively). Overall response rate was 50.0% in cohort I and 23.5% in cohort II (exploratory analysis, P=0.014). Median times to tumour progression and overall survival were 5.6 and 10.1 months in cohort I and 3.7 and 7.2 months in cohort II, respectively. Dose reductions for docetaxel and capecitabine were required in 50.0% and 57.5% of patients in cohort I and 11.8% and 15.7% in cohort II, respectively.

Conclusion:

Starting treatment with full doses and reducing promptly seems to be the more promisingly effective strategy than starting cautiously with lower doses. Docetaxel/capecitabine 75/2000 mg m⁻² is a manageable, convenient outpatient combination with promising efficacy against advanced gastric cancer.     

Preoperative downstaging chemoradiation with concurrent irinotecan and capecitabine in MRI-defined locally advanced rectal cancer: a phase I trial (NWCOG-2)

Background:

The aim of this study was to investigate the safety of neoadjuvant chemoradiation using radiotherapy (RT) combined with concurrent capecitabine and irinotecan for locally advanced rectal cancer before surgery.

Methods:

Forty-six patients were recruited and treated on the basis that MRI scanning had shown poor-risk tumours with threatening (⩽1 mm) or involvement of the mesorectal fascia. Conformal RT was given using 3 or 4 fields at daily fractions of 1.8 Gy on 5 days per week to a total dose of 45 Gy. Concurrently oral capecitabine was given twice daily throughout radiotherapy continuously from days 1 to 35 and intravenous irinotecan was given once per week during weeks 1 to 4 of RT. Dose levels were gradually escalated as follows. Dose level 1: capecitabine 650 mg m⁻² b.i.d. and irinotecan 50 mg m⁻²; Dose level 2: capecitabine 650 mg m⁻² b.i.d. and irinotecan 60 mg m⁻²; Dose level 3: capecitabine 825 mg m⁻² b.i.d. and irinotecan 60 mg m²; Dose level 4: capecitabine 825 mg m⁻² b.i.d. and irinotecan 70 mg m⁻².

Results:

Diarrhoea (grade 3, no grade 4) was the main serious acute toxicity with lesser degrees of fatigue, neutropenia, anorexia and palmar-plantar erythrodysesthesia. The recommended dose for future study was dose level 2 at which 3 of 14 patients (21%) developed grade 3 diarrhoea. Postoperative complications included seven pelvic or wound infections and two anastomotic and two perineal wound dehiscences. There were no deaths in the first 30 days postoperatively. Of 41 resected specimens, 11 (27%) showed a pathological complete response (pCR) and five (12%) showed an involved circumferential resection margin (defined as ⩽1 mm). The 3-year disease-free survival (intent-to-treat) was 53.2%.

Conclusion:

In patients with poor-risk MRI-defined locally advanced rectal cancer threatening or involving the mesorectal fascia, preoperative chemoradiation based on RT at 45 Gy in 25 daily fractions over 5 weeks with continuous daily oral capecitabine at 650 mg m⁻² b.i.d. days 1–35 and weekly IV irinotecan at 60 mg m⁻² weeks 1–4, provides acceptable acute toxicity and postoperative morbidity with encouraging response and curative resection rates.     

Dose-finding study and pharmacogenomic analysis of fixed-rate infusion of gemcitabine, irinotecan and bevacizumab in pretreated metastatic colorectal cancer patients

Background:

To determine the dose-limiting toxicity (DLT), maximum tolerated dose, recommended dose (RD) and preliminary evidence of activity of escalating doses of irinotecan (CPT-11) fixed-dose-rate infusional gemcitabine (FDR-GMB) and bevacizumab in pretreated metastatic colorectal cancer (mCRC) patients. Pharmacogenomic analysis was performed to investigate the association between VEGF single-nucleotide polymorphisms and clinical outcome.

Patients and methods:

A total of 89 mCRC patients were recruited in a two-step study design; 28 were included in the dose-finding study and 59 in the pharmacogenomic analysis. The FDR-GMB of 1000 mg m^–2, bevacizumab 5 mg kg^–1 and CPT-11 doses ranging from 100 to 160 mg m^–2 were explored. The VEGF protein serum levels were quantified by EIA. Allelic discrimination was performed to genotype polymorphisms in the VEGF gene.

Results:

CPT-11 RD was 150 mg m^–2. Diarrhoea and neutropenia were the DLT. After a median follow-up of 42 months, the median time to progression (TTP) and overall survival were 5.2 and 19.9 months, respectively. VEGF levels were significantly correlated with VEGF-2578AA and VEGF-460CC genotypes, and a trend was observed with VEGF+405GG genotype. The presence of any of these genotypes correlated with a longer median TTP (8.8 vs 4.5 months, P=0.04).

Conclusion:

The triplet combination tested in this study is effective and well tolerated. A possible predictive role for VEGF gene polymorphisms and baseline VEGF circulating levels is suggested.     

Randomised, non-comparative phase II study of weekly docetaxel with cisplatin and 5-fluorouracil or with capecitabine in oesophagogastric cancer: the AGITG ATTAX trial

Background:

Docetaxel administered 3-weekly with cisplatin and 5-fluorouracil leads to better survival than does standard therapy in patients with oesophagogastric cancer, but leads to high rates of haematological toxicity. Weekly docetaxel is associated with less haematological toxicity. This randomised phase II study tested weekly docetaxel-based combination chemotherapy regimens, with the aim of maintaining their activity while reducing toxicity.

Methods:

Patients with histologically confirmed metastatic oesophageal or gastric carcinoma were randomised to receive weekly docetaxel (30 mg m⁻²) on days 1 and 8, cisplatin (60 mg m⁻²) on day 1, and 5-fluorouracil (200 mg m⁻² per day) continuously, every 3 weeks (weekly TCF, wTCF); or docetaxel (30 mg m⁻²) on days 1 and 8 and capecitabine (1600 mg m⁻² per day) on days 1–14, every 3 weeks (weekly TX, wTX).

Results:

A total of 106 patients were enrolled (wTCF, n=50; wTX, n=56). Response rates, the primary end point, were 47% with wTCF and 26% with wTX. Rates of febrile neutropenia were low in each arm. Median progression-free and overall survival times were 5.9 and 11.2 months for wTCF and 4.6 and 10.1 months for wTX, respectively.

Conclusion:

Weekly TCF and TX have encouraging activity and less haematological toxicity than TCF administered 3-weekly. Weekly docetaxel-based combination regimens warrant further evaluation in this disease.     

Toxicity associated with capecitabine plus oxaliplatin in colorectal cancer before and after an institutional policy of capecitabine dose reduction

Background:

Capecitabine plus oxaliplatin (CAPOX) is an established treatment option in colorectal cancer, but can be associated with severe toxicities.

Methods:

Following reporting of severe diarrhoea and dehydration with capecitabine 2000 mg m^–2 per day plus oxaliplatin every 3 weeks (CAPOX 2000) in 2006, we instituted a policy change to reduce capecitabine dose to 1700 mg m^–2 per day (CAPOX 1700). We undertook a retrospective analysis comparing toxicities encountered before and after this dose change.

Results:

Of the 400 patients treated, no significant differences were seen between the CAPOX 2000 and CAPOX 1700 in grades 3 and 4 diarrhoea (21% vs 19% P=0.80), stomatitis (0% vs 1% P=0.50) or grades 2–4 hand foot syndrome (16% vs 11% P=0.18). Grades 3 and 4 neutropenia (9.5% vs 3.5% P=0.03) and all grades hyperbilirubinaemia (60% vs 40% P<0.0001) were significantly reduced with CAPOX 1700. Rates of hospitalisation due to toxicities were not different between two groups (13% vs 11% P=0.53).

Conclusions:

No clinically or statistically significant differences in gastrointestinal toxicities or hospitalisation rate were seen after reducing our routine capecitabine dose from CAPOX 2000 to CAPOX 1700.     

Efficacy and tolerability of bevacizumab plus capecitabine as first-line therapy in patients with advanced hepatocellular carcinoma

Background:

Molecularly targeted agents with anti-angiogenic activity, including bevacizumab, have demonstrated clinical activity in patients with advanced/metastatic hepatocellular carcinoma (HCC). This multicentre phase II study involving patients from several Asian countries sought to evaluate the safety and efficacy of bevacizumab plus capecitabine in this population.

Methods:

Histologically proven/clinically diagnosed advanced HCC patients received bevacizumab 7.5 mg kg^–1 on day 1 and capecitabine 800 mg m^–2 twice daily on days 1–14 every 3 weeks as first-line therapy.

Results:

A total of 45 patients were enrolled; 44 (96%) had extrahepatic metastasis and/or major vessel invasion and 30 (67%) had hepatitis B. No grade 3/4 haematological toxicity occurred. Treatment-related grade 3/4 non-haematological toxicities included diarrhoea (n=2, 4%), nausea/vomiting (n=1, 2%), gastrointestinal bleeding (n=4, 9%) and hand–foot syndrome (n=4, 9%). The overall response rate (RECIST) was 9% and the disease control rate was 52%. Overall, median progression-free survival (PFS) and overall survival (OS) were 2.7 and 5.9 months, respectively. Median PFS and OS were 3.6 and 8.2 months, respectively, for Cancer of the Liver Italian Programme (CLIP) score ⩽3 patients, and 1.4 and 3.3 months, respectively, for CLIP score 4 patients.

Conclusion:

The bevacizumab–capecitabine combination shows good tolerability and modest anti-tumour activity in patients with advanced HCC.     

Phase I clinical trial of the Src inhibitor dasatinib with dacarbazine in metastatic melanoma

Background:

Src inhibitors sensitise melanoma cells to chemotherapy in preclinical models. The combination of dasatinib and dacarbazine was tested in a phase I trial in melanoma.

Methods:

Patients had ECOG performance status 0–2 and normal organ function. Dacarbazine was administered on day 1 and dasatinib on day 2 through 19 of each 21-day cycle. Both were escalated from 50 mg b.i.d. of dasatinib and 800 mg m⁻² of dacarbazine. Available pre-treatment biopsies were sequenced for BRAF, NRAS, and C-Kit mutations.

Results:

Dose-limiting toxicity was reached at dasatinib 70 mg b.i.d./dacarbazine 1000 mg m⁻², and was predominantly haematological. In 29 patients receiving dasatinib 70 mg b.i.d., the objective response rate (ORR) was 13.8%, the clinical benefit rate (ORR+SD) was 72.4%, the 6-month progression-free survival (PFS) was 20.7%, and the 12-month overall survival (OS) was 34.5%. Two out of three patients who were wild type for BRAF, NRAS, and c-KIT mutations had confirmed partial responses, and one had a minor response.

Conclusion:

The recommended phase II dose is dasatinib70 mg b.i.d with dacarbazine 800 mg m⁻². PFS and OS data for dasatinib at 70 mg b.i.d. with dacarbazine compared favourably with historical controls. Preliminary data support evaluating tumour mutation status further as a biomarker of response.     

A randomised, phase II study of intetumumab, an anti-αv-integrin mAb, alone and with dacarbazine in stage IV melanoma

Background:

α_v integrins are involved in angiogenesis and melanoma tumourigenesis. Intetumumab (CNTO 95) is a fully human anti-α_v-integrin monoclonal antibody.

Methods:

In a multicentre, randomised, phase II study, stage IV melanoma patients were randomised 1 : 1 : 1 : 1 to 1000 mg m⁻² dacarbazine+placebo (n=32), 1000 mg m⁻² dacarbazine+10 mg kg⁻¹ intetumumab (n=32), 10 mg kg⁻¹ intetumumab (n=33), or 5 mg kg⁻¹ intetumumab (n=32) q3w. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), adverse events, and pharmacokinetics.

Results:

No statistically significant differences in efficacy were observed between groups. In the dacarbazine+placebo, dacarbazine+intetumumab, 10 mg kg⁻¹ intetumumab, and 5 mg kg⁻¹ intetumumab groups, median PFS was 1.8, 2.5, 1.4, and 1.4 months; median OS was 8, 11, 15, and 9.8 months; and ORR of complete+partial response was 10, 3, 6, and 0%. Nonlinear intetumumab pharmacokinetics and potential intetumumab–dacarbazine interactions were observed. Transient, asymptomatic, nonrecurring, grade 1–2, uveitic reactions that resolved spontaneously or with topical steroids were seen in 22–30% of intetumumab-treated patients. Low-grade infusion-reaction symptoms (headache, fatigue, nausea, vomiting, fever, chills) were observed, as expected, in 16–73% of dacarbazine-treated patients. No intetumumab-related myelosuppression, laboratory/electrocardiogram abnormalities, or deaths occurred.

Conclusion:

With its favourable safety profile and a nonsignificant trend towards improved OS, intetumumab merits further investigation in advanced melanoma.     

The GOFURTGO Study: AGITG phase II study of fixed dose rate gemcitabine-oxaliplatin integrated with concomitant 5FU and 3-D conformal radiotherapy for the treatment of localised pancreatic cancer

Background:

Locally advanced inoperable pancreatic cancer (LAPC) has a poor prognosis. By increasing intensity of systemic therapy combined with an established safe chemoradiation technique, our intention was to enhance the outcomes of LAPC. In preparation for phase III evaluation, the feasibility and efficacy of our candidate regimen gemcitabine–oxaliplatin chemotherapy with sandwich 5-fluorouracil (5FU) and three-dimensional conformal radiotherapy (3DCRT) needs to be established.

Methods:

A total of 48 patients with inoperable LAPC without metastases were given gemcitabine (1000 mg m⁻² d1 + d15 q28) and oxaliplatin (100 mg m⁻² d2 + d16 q28) in induction (one cycle) and consolidation (three cycles), and 5FU 200 mg m⁻² per day over 6 weeks during 3DCRT 54 Gy.

Results:

Median duration of sustained local control (LC) was 15.8 months, progression-free survival (PFS) was 11.0 months, and overall survival was 15.7 months. Survival rates for 1, 2, and 3 years were 70.2%, 21.3%, and 12.8%, respectively. Global quality of life did not significantly decline from baseline during treatment, which was associated with modest treatment-related toxicity.

Conclusion:

Fixed-dose gemcitabine and oxaliplatin, combined with an effective and safe regimen of 5FU and 3DCRT radiotherapy, was feasible and reasonably tolerated. The observed improved duration of LC and PFS with more intensive therapy over previous trials may be due to patient selection, but suggest that further evaluation in phase III trials is warranted.     

Capecitabine in combination with irinotecan (XELIRI), administered as a 2-weekly schedule, as first-line chemotherapy for patients with metastatic colorectal cancer: a phase II study of the Spanish GOTI group

Background:

Combination chemotherapy is standard treatment for metastatic colorectal cancer (MCRC). The aim of this study was to determine the efficacy and safety of capecitabine+irinotecan (2-weekly schedule), as first-line therapy of MCRC.

Methods:

Patients received irinotecan 175 mg m⁻² on day 1 and oral capecitabine 1000 mg m⁻² twice daily on days 2–8 every 2 weeks. For patients aged ⩾65 years, the starting doses of irinotecan and capecitabine were reduced to 140 and 750 mg m⁻², respectively.

Results:

A total of 53 patients were enrolled: 29 (55%) were ⩾65 years old. In an intention-to-treat analysis, complete response was achieved in three patients for an overall response rate (ORR) of 32%. The disease control rate (ORR + stable disease) was 66% and the median duration of response was 7.3 months. Median time to progression and overall survival were 9.0 and 19.2 months, respectively. Grade 4 neutropenia was reported in one patient: no other grade 4 toxicities were recorded. Grade 3 diarrhoea occurred in 8 (15%) patients and grade 1–2 hand–foot syndrome in 7 (13%) patients.

Conclusion:

Capecitabine and irinotecan, given every 2 weeks, as first-line treatment of MCRC is an active regimen with a manageable toxicity profile, even in older patients.     

A multicentre randomised phase II trial of gemcitabine alone vs gemcitabine and S-1 combination therapy in advanced pancreatic cancer: GEMSAP study

Background:

This randomised phase II trial compared gemcitabine alone vs gemcitabine and S-1 combination therapy in advanced pancreatic cancer.

Methods:

Patients were randomly assigned to 4-week treatment with gemcitabine alone (1000, mg m⁻² gemcitabine by 30-min infusion on days 1, 8, and 15) or gemcitabine and S-1 combination therapy (1000, mg m⁻² gemcitabine by 30-min infusion on days 1 and 15 and 40 mg m⁻² S-1 orally twice daily on days 1–15). The primary end point was progression-free survival (PFS).

Results:

Between July 2006 and February 2009, 106 patients were enrolled. The PFS in gemcitabine and S-1 combination arm was significantly longer than in gemcitabine arm (5.4 vs 3.6 months), with a hazard ratio of 0.64 (P=0.036). Overall survival (OS) for gemcitabine and S-1 combination was longer than that for gemcitabine monotherapy (13.5 vs 8.8 months), with a hazard ratio of 0.72 (P=0.104). Overall, grade 3 or 4 adverse events were similar in both arms.

Conclusion:

Gemcitabine and S-1 combination therapy demonstrated longer PFS in advanced pancreatic cancer. Improved OS duration of 4.7 months was found for gemcitabine and S-1 combination therapy, though this was not statistically significant.     

Phase II and UGT1A1 genotype study of irinotecan dose escalation as salvage therapy for advanced gastric cancer

Background:

To assess the efficacy and safety of individualised dose optimisation of irinotecan monotherapy as salvage treatment for advanced gastric cancer (AGC).

Methods:

A total of 43 patients were enrolled. Intravenous irinotecan (350 mg m⁻²) was administered every 3 weeks. The dose was increased (425 mg m⁻² and 500 mg m⁻²) or decreased (250 mg m⁻²) depending on patient tolerance. UGT1A1 genotypes were determined by direct sequencing of genomic DNA extracted from peripheral blood.

Results:

A total of 183 cycles of irinotecan were administered, with a median of four cycles per patient. The overall response rate was 9.3%, and the disease control rate was 62.8%. Median time to disease progression was 2.8 months, and median overall survival was 8.0 months. Grade 3–4 neutropenia was the most common toxicity (53.5%), and febrile neutropenia was the least common toxicity (4.6%). Compared with defective allele groups, UGT1A1 *1/*1 was associated with a lower incidence of grade 3–4 neutropenia during the first cycle (P=0.018).

Conclusion:

Individualised irinotecan dose escalation based on patient tolerance was not associated with increased toxicity and shows modest activity as salvage chemotherapy for AGC. The role of UGT1A1 genotype in clinical toxicity requires further evaluation.     

Docetaxel combined with irinotecan or 5-fluorouracil in patients with advanced oesophago-gastric cancer: a randomised phase II study

Background:

Docetaxel and irinotecan chemotherapy have shown good efficacy in the treatment of advanced oesophago-gastric cancer. This randomised phase II study evaluated the efficacy and toxicity profile of two non-platinum docetaxel-based doublet regimens in advanced oesophago-gastric cancer.

Methods:

Chemotherapy-naïve patients with advanced oesophago-gastric cancer were randomised to receive either 3-weekly DI (docetaxel 60 mg m⁻² plus irinotecan 250 mg m⁻² (Day 1)) or 3-weekly DF (docetaxel 85 mg m⁻² (Day 1) followed by 5-fluorouracil 750 mg m⁻² per day as a continuous infusion (Days 1–5)).

Results:

A total of 85 patients received DI (n=42) or DF (n=43). The primary endpoint was overall response rate (ORR). The ORR and time to progression (TTP) in the evaluable population (n=65) were 37.5% (DI) vs 33.3% (DF), and 4.2 months vs 4.4 months, respectively. In the intent-to-treat population, the observed ORR, TTP and median overall survival were similar between the two groups. Grade 3–4 neutropenia, febrile neutropenia and diarrhoea were more frequent in the DI arm as compared with the DF arm (83.3% vs 69.8%, 40.5% vs 18.6%, and 42.9% vs 16.3%, respectively).

Conclusion:

Both docetaxel-based doublet regimens show comparable efficacy; however, the DF regimen was associated with a better toxicity profile and is an alternative treatment option for patients in whom platinum-based regimens are unsuitable.     

A genotype-directed phase I-IV dose-finding study of irinotecan in combination with fluorouracil/leucovorin as first-line treatment in advanced colorectal cancer

Background:

Infusional fluorouracil/leucovorin (FU/LV) plus irinotecan (FOLFIRI) is one of the standard first-line options for patients with metastatic colorectal cancer (mCRC). Irinotecan is converted into 7-ethyl-10-hydroxycamptothecin (SN-38) by a carboxylsterase and metabolised through uridine diphosphate glucuronosyl transferase (UGT1A1). The UGT1A1^*28 allele has been associated with the risk of developing severe toxicities. The present trial was designed to define the maximum tolerated dose according to UGT1A1 genotype. This report focuses on the results of tolerance to different escalated doses of FOLFIRI first-line of chemotherapy.

Patients and methods:

Patients undergoing first-line treatment for mCRC and eligible for treatment with FOLFIRI were classified according to UGT1A1 genotype. A total of 94 patients were eligible for dose escalation of irinotecan. The starting dose of biweekly irinotecan was 180 mg m⁻² for the ^*1/^*1, 110 mg m⁻² for the ^*1/^*28 and 90 mg m⁻² for the ^*28/^*28 genotypes.

Results:

The dose of irinotecan was escalated to 450 mg m⁻² in patients with the ^*1/^*1 genotype, to 390 mg m⁻² in those with the ^*1/^*28 genotype and to 150 mg m⁻² in those with the ^*28/^*28 genotype. Neutropenia and diarrhoea were the most common grade 3 or 4 toxicities.

Conclusions:

Our results demonstrated that the recommended dose of 180 mg m⁻² for irinotecan in FOLFIRI is considerably lower than the dose that can be tolerated for patients with the UGT1A1 ^*1/^*1 and ^*1/^*28 genotypes. The maximum tolerable dose (MTD) in patients with a high-risk UGT1A1 ^*28/^*28 genotype is 30% lower than the standard dose of 180 mg m⁻².     

Docetaxel and epirubicin compared with docetaxel and prednisone in advanced castrate-resistant prostate cancer: a randomised phase II study

Background:

This randomised phase II study compared the activity and safety of the combination docetaxel (D)/epirubicin (EPI) with the conventional treatment D/prednisone (P) in advanced castrate-resistant prostate cancer (CRPC) patients.

Materials and methods:

Patients were randomly assigned to D 30 mg m⁻² as intravenous infusion (i.v.) and EPI 30 mg m⁻² i.v. every week (D/EPI arm), or D 70 mg m⁻² i.v. every 3 weeks and oral P 5 mg twice daily (D/P arm). Chemotherapy was administered until disease progression or unacceptable toxicity.

Results:

A total of 72 patients were enrolled in the study and randomly assigned to treatment: 37 to D/EPI and 35 to D/P. The median progression-free survival (PFS) was 11.1 months (95% CI 9.2–12.6 months) in the D/EPI arm and 7.7 months (95% CI 5.7–9.4 months) in the D/P arm (P=0.0002). The median survival was 27.3 months (95% CI 22.1–30.8 months) in the D/EPI arm and 19.8 months (95% CI 14.4–24.8 months) in the D/P arm (P=0.003). Both regimens were generally well tolerated.

Conclusion:

The treatment of advanced CRPC with weekly D combined with weekly EPI was feasible and tolerable, and led to superior PFS than the treatment with 3-weekly D and oral P.     

A phase-II trial of dose-dense chemotherapy in patients with disseminated thymoma: report of a Japan Clinical Oncology Group trial (JCOG 9605)

Background:

To evaluate the safety and efficacy of dose-dense weekly chemotherapy in the treatment of advanced thymoma.

Methods:

Subjects comprised patients with histologically documented chemotherapy-naïve thymoma with stage-IVa or IVb disease. Thymic carcinoma, carcinoid or lymphoma cases were excluded. Patients received 9 weeks of chemotherapy: cisplatin (25 mg m⁻²) on weeks 1–9; vincristine (1 mg m⁻²) on weeks 1, 2, 4, 6 and 8; and doxorubicin (40 mg m⁻²) and etoposide (80 mg m⁻²) on days 1–3 of weeks 1, 3, 5, 7 and 9. Chemotherapy courses were supported by granulocyte colony-stimulating factor. Post-protocol local therapy was allowed.

Results:

From July 1997 to March 2004, 30 patients were entered. Three were ineligible due to different histology. Chemotherapy-associated toxicity was mainly haematological and was well tolerated, with no deaths due to toxicity, and 87% of patients completed the planned 9-week regimen. Overall response rate was 59%, with 16 of the 27 eligible patients achieving partial response. Median progression-fee survival (PFS) was 0.79 years (95% confidence interval: 0.52–1.40 years), and PFS at 1 and 2 years was 37 and 15%, respectively. Overall survival rates at 2 and 5 years were 89 and 65%, respectively.

Conclusion:

In stage-IV thymoma patients, weekly dose-dense chemotherapy offers similar activity to conventional regimens.     

Gemcitabine, oxaliplatin and 5-FU in advanced bile duct and gallbladder carcinoma: two parallel, multicentre phase-II trials

Background:

Gemcitabine, oxaliplatin and 5-fluorouracil (5-FU) are active in biliary tract cancer and have a potentially synergistic mode of action and non-overlapping toxicity. The objective of these trials was to determine response, survival and toxicity separately in patients with bile duct cancer (BDC) and gallbladder cancer (GBC) treated with gemcitabine/oxaliplatin/5-FU chemotherapy.

Methods:

Eligible patients with histologically proven, advanced or metastatic BDC (n=37) or GBC (n=35) were treated with gemcitabine (900 mg m⁻² over 30 min), oxaliplatin (65 mg m⁻²) and 5-FU (1500 mg m⁻² over 24 h) on days 1 and 8 of a 21-day cycle. Tumour response was the primary outcome measure.

Results:

Response rates were 19% (95% CI: 6–32%) and 23% (95% CI: 9–37%) for BDC and GBC, respectively. Median survivals were 10.0 months (95% CI: 8.6–12.4) and 9.9 months (95% CI: 7.5–12.2) for BDC and GBC, respectively, and 1- and 2-year survival rates were 40 and 23% in BDC and 34 and 6% in GBC (intention-to-treat analysis). Major grade III and IV adverse events were neutropenia, thrombocytopenia, elevated bilirubin and anorexia.

Conclusion:

Triple-drug chemotherapy achieves comparable results for response and survival to previously reported regimens, but with more toxicity.     

Phase II multi-institutional prospective randomised trial comparing S-1+paclitaxel with S-1+cisplatin in patients with unresectable and/or recurrent advanced gastric cancer

Background:

A combination of S-1 and cisplatin has been shown to be effective with acceptable safety for the first-line treatment of far-advanced gastric cancer in Japan. This is the first randomised phase II trial to compare S-1+paclitaxel with S-1+cisplatin in this setting.

Methods:

Patients with unresectable and/or recurrent advanced gastric cancer were randomly assigned to receive one of the two regimens: S-1 (40 mg m⁻² twice daily) on days 1–14 plus paclitaxel (60 mg m⁻²) on days 1, 8, and 15 of a 4-week cycle (S-1+paclitaxel) or S-1 (40 mg m⁻² twice daily) on days 1–21 plus cisplatin (60 mg m⁻²) on day 8 of a 5-week cycle (S-1+cisplatin). The primary end point was the response rate (RR). Secondary end points included progression-free survival (PFS), overall survival (OS), and safety.

Results:

A total of 83 patients were eligible for safety and efficacy analyses. In the S-1+paclitaxel and S-1+cisplatin groups, RRs (52.3% vs 48.7% P=0.74) and median PFS (9 vs 6 months; P=0.50) were similar. The median OS was similar in the S-1+paclitaxel and S-1+cisplatin groups (16 vs 17 months; P=0.84). The incidence of grade 3 or higher haematological toxicity was 19.0% with S-1+paclitaxel and 19.5% with S-1+cisplatin. The incidence of grade 3 or higher non-haematological toxicity was 14.2% with S-1+paclitaxel and 17.1% with S-1+cisplatin.

Conclusion:

S-1+paclitaxel was suggested to be a feasible and effective non-platinum-based regimen for chemotherapy in patients with advanced gastric cancer. Our results should be confirmed in multicenter, phase III-controlled clinical trials.