A multicenter phase III prospective randomized trial of high-dose epirubicin in combination with cyclophosphamide (EC) versus docetaxel followed by EC in node-positive breast cancer. GOIM (Gruppo Oncologico Italia Meridionale) 9902 study

BackgroundThe Gruppo Oncologico Italia Meridionale 9902 trial compared four cycles of high-dose epirubicin plus cyclophosphamide (EC) with four cycles of docetaxel (Taxotere, D) followed by four cycles of EC as adjuvant treatment of node-positive breast cancer.Patients and methodsPatients were randomly assigned to EC (E 120 mg/m², C 600 mg/m², arm A) for four cycles or four cycles of D (100 mg/m²) followed by four cycles of EC (arm B), both regimens every 21 days. Hormone receptor-positive patients were given hormonal therapy for 5 years. Primary end point was 5-year disease-free survival (DFS). Secondary objectives were overall survival (OS) and safety.ResultsThere were 750 patients enrolled. With a median follow-up of 64 months, 5-year DFS was 73.4% in both arms, and 5-year OS was 89.5% versus 90.7% in arm A and B [hazard ratio was 0.99 (95% confidence interval for DFS 0.75–1.31; P = 0.95)], respectively. Grade 3–4 toxicity was more common in arm B.ConclusionsThis study did not show advantages from the addition of docetaxel to high-dose EC as adjuvant chemotherapy in node-positive breast cancer. The small sample size and low number of DFS events may have limited the ability to observe statistically significant difference between the two arms.     

Epirubicin and cyclophosphamide versus epirubicin and docetaxel as first-line therapy for women with metastatic breast cancer: final results of a randomised phase III trial

BackgroundThis randomised phase III trial was carried out to compare the efficacy and safety of epirubicin and cyclophosphamide (EC) with epirubicin and docetaxel (Taxotere) (ED) as first-line chemotherapy for metastatic breast cancer.Patients and methodsPatients (n = 240) were randomly assigned to receive either ED (epirubicin 75 mg/m² and docetaxel 75 mg/m²) or EC (epirubicin 90 mg/m² and cyclophosphamide 600 mg/m²). The primary end point was objective response rate (ORR). Secondary end points were progression-free survival (PFS), overall survival (OS), and safety.ResultsORR for patients randomly assigned to receive EC and ED were 42% and 47%, respectively (P = 0.63). Median PFS [10.1 versus 10.3 months; hazard ratio (HR) 0.98; log-rank P = 0.38] and OS (19.9 versus 30.0 months; HR 0.663; log-rank P = 0.21) were comparable in both arms. Although grade 3/4 leucopenia occurred more frequently with ED (81% versus 73%; P = 0.01), there were no significant differences in the incidence of febrile neutropenia and grade 3/4 infections. Grade 3/4 non-haematologic toxicity was infrequent in both arms. Congestive heart failure was observed in one patient in each arm.ConclusionIn this randomised trial, no differences in the efficacy study end points were observed between the two treatment arms.     

Cetuximab plus cisplatin–5-fluorouracil versus cisplatin–5-fluorouracil alone in first-line metastatic squamous cell carcinoma of the esophagus: a randomized phase II study of the Arbeitsgemeinschaft Internistische Onkologie

BackgroundThis study assessed the activity of the mAb cetuximab in combination with cisplatin and 5-fluorouracil (5-FU) in advanced esophageal squamous cell carcinoma.Patients and methodsFor a maximum of six 29-day cycles, patients received cisplatin 100 mg/m², day 1, plus 5-FU 1000 mg/m², days 1–5 (CF), either alone or in combination with cetuximab (CET–CF; 400 mg/m² initial dose followed by 250 mg/m² weekly thereafter). The primary end point was tumor response. Tumor material was obtained for analysis of KRAS mutation status.ResultsSixty-two eligible patients were included, 32 receiving CET–CF and 30 CF. Cetuximab did not exacerbate grade 3/4 toxicity, except for rash (6% versus 0%) and diarrhea (16% versus 0%). The overall response rate according to RECIST criteria was 19% and 13% and the disease control rate 75% and 57% for the CET–CF and CF arms, respectively. With a median follow-up of 21.5 months, the median progression-free survival was 5.9 and 3.6 months and median overall survival 9.5 and 5.5 months for CET–CF and CF, respectively. No KRAS codon 12/13 tumor mutations were identified in 37 evaluated samples.ConclusionCetuximab can be safely combined with CF chemotherapy and may increase the efficacy of standard CF chemotherapy.     

Phase III trial comparing intensive induction chemoradiotherapy (60 Gy,infusional 5-FU and intermittent cisplatin) followed by maintenance gemcitabine with gemcitabine alone for locally advanced unresectable pancreatic cancer. Definitive results of the 2000–01 FFCD/SFRO study

BackgroundThe role of chemoradiation with systemic chemotherapy compared with chemotherapy alone in locally advanced pancreatic cancer (LAPC) is uncertain.Patients and methodsOne hundred and nineteen patients with LAPC, World Health Organization performance status of zero to two were randomly assigned to either the induction CHRT group (60 Gy, 2 Gy/fraction; concomitant 5-fluorouracil infusion, 300 mg/m²/day, days 1–5 for 6 weeks; cisplatin, 20 mg/m²/day, days 1–5 during weeks 1 and 5) or the induction gemcitabine group (GEM: 1000 mg/m² weekly for 7 weeks). Maintenance gemcitabine (1000 mg/m² weekly, 3/4 weeks) was given in both arms until disease progression or toxicity.ResultsOverall survival was shorter in the CHRT than in GEM arm [median survival 8.6 (99% confidence interval 7.1–11.4) and 13 months (8.7–18.1), P = 0.03]. One-year survival was, respectively, 32% and 53%. These results were confirmed in a per-protocol analysis for patients who received 75% or more of the planned dose of radiotherapy. More overall grades 3–4 toxic effects were recorded in the CHRT arm, both during induction (36 versus 22%) and maintenance (32 versus 18%).ConclusionThis intensive induction schedule of CHRT was more toxic and less effective than gemcitabine alone.     

A randomized phase II study of PEP02 (MM-398), irinotecan or docetaxel as a second-line therapy in patients with locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma

BackgroundPEP02 is a novel highly stable liposomal nanocarrier formulation of irinotecan. This randomized phase II study evaluated the efficacy and safety of single agent PEP02 compared with irinotecan or docetaxel in the second-line treatment of advanced oesophago-gastric (OG) cancer.Patients and methodsPatients with locally advanced/metastatic disease who had failed one prior chemotherapy regimen were randomly assigned to PEP02 120 mg/m², irinotecan 300 mg/m² or docetaxel (Taxotere) 75 mg/m² every 3 weeks. The primary end point was objective response rate (ORR). Simon's two-stage design was used and the ORR of interest was 20% (α = 0.05, type II error β = 0.10, null hypothesis of ORR was 5%).ResultsForty-four patients per arm received treatment, and 124 were assessable for response. The ORR statistical threshold for the first stage was reached in all arms. In the intent-to-treat (ITT) population, ORRs were 13.6% (6/44), 6.8% (3/44) and 15.9% (7/44) in the PEP02, irinotecan and docetaxel arms, respectively. The median progression-free survival (PFS) and overall survival were similar between the trial arms. Commonest grade 3–4 adverse event reported was diarrhoea in the PEP02 and irinotecan groups (27.3% versus 18.2%).ConclusionThe ORR associated with PEP02 was comparable with docetaxel and numerically greater than that of irinotecan. PEP02 warrants further evaluation in the advanced gastric cancer setting.     

A randomized phase III trial of oral S-1 plus cisplatin versus docetaxel plus cisplatin in Japanese patients with advanced non-small-cell lung cancer: TCOG0701 CATS trial

BackgroundPlatinum-based two-drug combination chemotherapy has been standard of care for patients with advanced nonsmall-cell lung cancer (NSCLC). The primary aim was to compare overall survival (OS) of patients with advanced NSCLC between the two chemotherapy regimens. Secondary end points included progression-free survival (PFS), response, safety, and quality of life (QoL).Patients and methodsPatients with previously untreated stage IIIB or IV NSCLC, an Eastern Cooperative Oncology Group performance status of 0–1 and adequate organ function were randomized to receive either oral S-1 80 mg/m²/day on days 1–21 plus cisplatin 60 mg/m² on day 8 every 4–5 weeks, or docetaxel 60 mg/m² on day 1 plus cisplatin 80 mg/m² on day 1 every 3–4 weeks, both up to six cycles.ResultsA total of 608 patients from 66 sites in Japan were randomized to S-1 plus cisplatin (n = 303) or docetaxel plus cisplatin (n = 305). OS for oral S-1 plus cisplatin was noninferior to docetaxel plus cisplatin [median survival, 16.1 versus 17.1 months, respectively; hazard ratio = 1.013; 96.4% confidence interval (CI) 0.837–1.227]. Significantly higher febrile neutropenia (7.4% versus 1.0%), grade 3/4 neutropenia (73.4% versus 22.9%), grade 3/4 infection (14.5% versus 5.3%), and grade 1/2 alopecia (59.3% versus 12.3%) were observed in the docetaxel plus cisplatin than in the S-1 plus cisplatin. There were no differences found in PFS or response between the two arms. QoL data investigated by EORTC QLQ-C30 and LC-13 favored the S-1 plus cisplatin.ConclusionOral S-1 plus cisplatin is not inferior to docetaxel plus cisplatin and is better tolerated in Japanese patients with advanced NSCLC.Clinical trial numberUMIN000000608.     

Induction or consolidation chemotherapy for unresectable stage III non-small-cell lung cancer patients treated with concurrent chemoradiation: a randomised phase II trial GFPC – IFCT 02-01

PurposeThe objective of this randomised phase II study was to evaluate the impact in terms of response and toxicities of induction or consolidation chemotherapy respectively before or after concurrent chemoradiotherapy in unresectable stage III non-small-cell lung cancer.Patients and methodsIn the induction arm, patients received induction chemotherapy with cisplatin (80 mg/m²) and paclitaxel (200 mg/m²) on days 1 and 29 followed by a concurrent chemoradiotherapy (66 Gy in 33 fractions, cisplatin 80 mg/m² days 1, 29 and 57, vinorelbine 15 mg/m² days 1, 8, 29, 36, 57 and 64). In consolidation arm, the same concurrent chemoradiotherapy began on day 1 followed by two cycles of cisplatin and paclitaxel.ResultsOne hundred twenty seven patients were randomised. The intent to treat response rates in induction and consolidation arms were 58% and 56% respectively. Median survival was 19.6 months in induction arm and 16.3 months in consolidation arm and 4-year survival rates were 21% and 30% respectively. Haematologic and non-haematologic toxicities were similar in both arms, except grade 3/4 oesophagitis, more frequent in consolidation arm than in induction arm (17% versus 10%).ConclusionCisplatin-based chemotherapy as induction or consolidation with concurrent chemoradiotherapy can be administrated safely. Response rates were similar in both arms with a trend in favour for consolidation arm for long-term survival.     

A randomized phase II study comparing induction or consolidation chemotherapy with cisplatin–docetaxel,plus radical concurrent chemoradiotherapy with cisplatin–docetaxel,in patients with unresectable locally advanced non-small-cell lung cancer

BackgroundIn stage III non-small-cell lung cancer (NSCLC), the role of systemic chemotherapy preceding or following concurrent chemo-radiotherapy (CT-RT) is unclear. We carried out a randomized phase II study to study the toxicity involved-field CT-RT with either induction or consolidation cisplatin–docetaxel (Taxotere).Patients and methodsPatients were randomly assigned to receive two cycles of docetaxel (D) 75 mg/m² on day 1 and cisplatin (C) 40 mg/m² on days 1 and 2, either preceding (IND arm) or following (CON arm) concurrent CT-RT, where 66 Gy was delivered using involved-fields concurrent with weekly D 20 mg/m² and C 20 mg/m². Patients at higher risk for lung toxicity (V₂₀ > 35%) crossed over to IND arm. Seventy patients were needed to exclude grade (G)3–4 esophagitis in >25%.ResultsOf the 70 eligible patients, 26 were treated in IND and 34 CON; five with V₂₀ >35% switched from CON to IND. The differences in G3–4 esophagitis observed (32/2% IND versus 21/3% CON) were not significantly different from the hypothesized 25% rate. Rates of G≥2 pneumonitis were similar, but IND arm had less G3–4 neutropenia. One-year survival was 63.2% [95% confidence interval (CI) 48.4% to 78.0%] and 65.5% (95% CI 48.2% to 82.8%) for the IND and CON arms, respectively.ConclusionBoth study arms merit further testing in patients with limited volume stage III NSCLC.     

Adjuvant chemotherapy with cisplatin and gemcitabine versus chemotherapy at relapse in patients with muscle-invasive bladder cancer submitted to radical cystectomy: an Italian,multicenter, randomized phase III trial

BackgroundThe purpose of the study was to evaluate the benefit of adjuvant chemotherapy (AC) versus surgery alone in patients with muscle-invasive bladder cancer (MIBC).Patients and methodsOne hundred and ninety-four patients with pT2G3, pT3–4, N0–2 transitional cell bladder carcinoma were randomly allocated to control (92 patients) or to four courses of AC (102 patients). These latter patients were further randomly assigned to receive gemcitabine 1000 mg/m² days 1, 8 and 15 and cisplatin 70 mg/m² day 2 or gemcitabine as above plus cisplatin 70 mg/m² day 15, every 28 days.ResultsAt a median follow-up of 35 months, the 5-year overall survival (OS) was 48.5%, with no difference between the two arms [P = 0.24, hazard ratio (HR) 1.29, 95% confidence interval (CI) 0.84–1.99]. Mortality hazard was significantly correlated with Nodes (N) and Tumor (T) stage. The control and AC arms had comparable disease-free survival (42.3% and 37.2%, respectively; P = 0.70, HR 1.08, 95% CI 0.73–1.59). Only 62% of patients received the planned cycles. A significant higher incidence of thrombocytopenia was observed in patients receiving cisplatin on day 2 (P = 0.006). A similar global quality of life was observed in the two arms.ConclusionThe study was underpowered to demonstrate that AC with cisplatin and gemcitabine improves OS and disease-free survival in patients with MIBC.     

Randomized Phase II Trial Comparing Chemoradiotherapy with Chemotherapy for Completely Resected Unsuspected N2-Positive Non–Small Cell Lung Cancer

IntroductionWe investigated whether concurrent chemoradiotherapy (CCRT) would increase survival in patients with completely resected unsuspected N2-positive NSCLC versus in patients who received adjuvant chemotherapy alone.MethodsEligible patients were randomly assigned (1:1) to either the CCRT arm or the chemotherapy arm. In the CCRT arm, patients received concurrent thoracic radiotherapy (50 Gy in 25 fractions) with five cycles of weekly paclitaxel (50 mg/m²) and cisplatin (25 mg/m²), followed by two additional cycles of paclitaxel (175 mg/m²) plus cisplatin (80 mg/m²) at 3-week intervals. In the chemotherapy arm, patients received four cycles of adjuvant paclitaxel (175 mg/m²) and carboplatin (area under the curve = 5.5) every 3 weeks. The primary end point was disease-free survival.ResultsWe enrolled and analyzed 101 patients (51 received CCRT and 50 received chemotherapy). In all, 74 and 27 patients were preoperatively staged as N0 and N1 diseases, respectively. The baseline characteristics were well balanced between the two arms. The median disease-free survival of the CCRT arm was 24.7 months, which was not significantly different from that of the chemotherapy arm (21.9 months) (hazard ratio = 0.94, 95% confident interval: 0.58–1.52, p = 0.40). There was no difference in overall survival (74.3 months in CCRT arm and 83.5 months in the chemotherapy arm) (hazard ratio = 1.33, 95% confident interval: 0.71–2.49).ConclusionsThere was no survival benefit from adjuvant CCRT compared with from platinum-based chemotherapy alone for completely resected unsuspected N2-positive NSCLC. However, the role of sequential radiotherapy administered after adjuvant chemotherapy is being evaluated, and further study is needed to evaluate the optimal radiotherapy approach for completely resected N2-positive NSCLC.     

Neoadjuvant chemotherapy followed by chemoradiation and surgery with and without cetuximab in patients with resectable esophageal cancer: a randomized,open-label,phase III trial (SAKK 75/08)

BackgroundThis open-label, phase III trial compared chemoradiation followed by surgery with or without neoadjuvant and adjuvant cetuximab in patients with resectable esophageal carcinoma.Patients and methodsPatients were randomly assigned (1 : 1) to two cycles of chemotherapy (docetaxel 75 mg/m², cisplatin 75 mg/m²) followed by chemoradiation (45 Gy, docetaxel 20 mg/m² and cisplatin 25 mg/m², weekly for 5 weeks) and surgery, with or without neoadjuvant cetuximab 250 mg/m² weekly and adjuvant cetuximab 500 mg/m² fortnightly for 3 months. The primary end point was progression-free survival (PFS).ResultsIn total, 300 patients (median age, 61 years; 88% male; 63% adenocarcinoma; 85% cT3/4a, 90% cN+) were assigned to cetuximab (n = 149) or control (n = 151). The R0-resection rate was 95% for cetuximab versus 97% for control. Postoperative treatment-related mortality was 6% in both arms. Median PFS was 2.9 years [95% confidence interval (CI), 2.0 to not reached] with cetuximab and 2.0 years (95% CI, 1.5–2.8) with control [hazard ratio (HR), 0.79; 95% CI, 0.58–1.07; P = 0.13]. Median overall survival (OS) time was 5.1 years (95% CI, 3.7 to not reached) versus 3.0 years (95% CI, 2.2–4.2) for cetuximab and control, respectively (HR, 0.73; 95% CI, 0.52–1.01; P = 0.055). Time to loco-regional failure after R0-resection was significantly longer for cetuximab (HR 0.53; 95% CI, 0.31–0.90; P = 0.017); time to distant failure did not differ between arms (HR, 1.01; 95% CI, 0.64–1.59, P = 0.97). Cetuximab did not increase adverse events in neoadjuvant or postoperative settings.ConclusionAdding cetuximab to multimodal therapy significantly improved loco-regional control, and led to clinically relevant, but not-significant improvements in PFS and OS in resectable esophageal carcinoma.Clinical trial informationNCT01107639     

Preoperative chemotherapy in advanced resectable OCSCC: long-term results of a randomized phase III trial

BackgroundData on preoperative chemotherapy in resectable oral cavity cancer are conflicting. We present the long-term results of a randomized trial of induction chemotherapy in resectable oral cavity cancer.Patients and MethodsA randomized, parallel, multicentre trial evaluated the impact of three cycles of cisplatin 100 mg/m² and fluorouracil 1000 mg/m² (120-h infusion administered every 21 days) in stage T2–T4, N0–N2, previously untreated patients with advanced disease. Control group received upfront surgery. Postoperative radiation was offered to both arms when pathologic risk features were identified. The co-primary end points were the occurrence of locoregional or distant tumour relapse, and death.ResultsAmong the 198 enrolled patients, with a median follow-up of 11.5 years, there was no difference in the incidence of locoregional relapse between chemotherapy and control group (P = 0.6337), nor in distant metastasis development (P = 0.1527). There was also no difference between groups in overall survival (P = 0.3402). Patients with a pathological complete response (pCR) had higher probability of survival than those without (10-year OS: 76.2% versus 41.3%, P = 0.0004). Late toxicities in patients with a minimum follow-up of 60 months (42 in each group) were similar between arms, except from fibrosis (cumulative incidence 40% versus 22% in chemotherapy arm) and grade 2 dysphagia (14% versus 5%).ConclusionsLong-term follow-up of this randomized trial confirmed the absence of survival benefit with preoperative chemotherapy in oral cavity cancer. Late toxicity was similar in the two arms except for fibrosis and dysphagia, which were less in the chemotherapy arm. The survival benefit for patients achieving a pCR was maintained.     

Preoperative versus postoperative docetaxel–cisplatin–fluorouracil (TCF) chemotherapy in locally advanced resectable gastric carcinoma: 10-year follow-up of the SAKK 43/99 phase III trial

BackgroundFluorouracil-based adjuvant chemotherapy in gastric cancer has been reported to be effective by several meta-analyses. Perioperative chemotherapy in locally advanced resectable gastric cancer (RGC) has been reported improving survival by two large randomized trials and recent meta-analyses but the role of neoadjuvant chemotherapy and optimal regimen remains to be determined. We compared a neoadjuvant with adjuvant docetaxel-based regimen in a prospective randomized phase III trial, of which we present the 10-year follow-up data.Patients and methodsPatients with cT3–4 anyN M0 or anyT cN1–3 M0 gastric carcinoma, staged with endoscopic ultrasound, computed tomography, bone scan, and laparoscopy, were assigned to receive four 21-day/cycles of docetaxel 75 mg/m² day 1, cisplatin 75 mg/m² day 1, and fluorouracil 300 mg/m²/day over days 1–14, either before (arm A) or after (arm B) gastrectomy. Event-free survival was the primary end point, whereas secondary end points included overall survival, toxicity, down-staging, pathological response, quality of life, and feasibility of adjuvant chemotherapy.ResultsThis trial was activated in November 1999 and closed in November 2005 due to insufficient accrual. Of the 70 enrolled patients, 69 were randomized, 34 to arm A and 35 to arm B. No difference in EFS (2.5 years in both arms) or OS (4.3 versus 3.7 years, in arms A and B, respectively) was found. A higher dose intensity of chemotherapy was observed in arm A and more frequent chemotherapy-related serious adverse events occurred in arm B. Surgery was safe after preoperative chemotherapy. A 12% pathological complete response was observed in arm A.ConclusionDocetaxel/cisplatin/fluorouracil chemotherapy is promising in preoperative setting of locally advanced RGC. The early stopping could mask the real effectiveness of neoadjuvant treatment. However, the complete pathological tumour responses, feasibility, and safe surgery warrant further investigation of a taxane-based regimen in the preoperative setting.     

Randomized phase II non-inferiority study (NO16853) of two different doses of capecitabine in combination with docetaxel for locally advanced/metastatic breast cancer

BackgroundThis phase II study investigated whether a lower-than-approved dose of capecitabine, plus docetaxel (XT), would improve tolerability versus standard-dose XT without compromising efficacy.Patients and methodsWomen aged ≥18 years with locally advanced/metastatic breast cancer resistant to anthracycline-based chemotherapy in the (neo)adjuvant, first- or second-line metastatic setting were eligible. Patients were randomly assigned to receive standard-dose XT (capecitabine 1250 mg/m² twice daily, days 1–14; docetaxel 75 mg/m², day 1 every 3 weeks) or low-dose XT (capecitabine 825 mg/m² twice daily, days 1–14; docetaxel as above). The primary objective was to demonstrate non-inferiority of low-dose to standard-dose XT in terms of progression-free survival (PFS).Results470 patients were randomly allocated in a 1 : 1 ratio to standard-dose or low-dose XT. Median PFS was 7.9 versus 5.8 months [hazard ratio 1.16, 95% confidence interval (CI) 0.95–1.43] in the standard-dose and low-dose arms, respectively. The upper limit of the 95% CI was above the predefined non-inferiority margin (1.35, P = 0.078). Secondary efficacy end points were consistent with PFS. The frequency and severity of adverse events was similar in both treatment arms.ConclusionsNon-inferiority of low-dose to standard-dose XT in terms of PFS was not demonstrated; this may be due to regional subgroup effects.     

Phase II Trial of Nab-Paclitaxel Compared With Docetaxel as First-Line Chemotherapy in Patients With Metastatic Breast Cancer: Final Analysis of Overall Survival

BackgroundA randomized phase II study in first-line MBC demonstrated superior efficacy and safety of weekly nab-paclitaxel compared with docetaxel. Final survival analyses and updated safety results are reported.Patients and MethodsThree hundred two patients with no previous chemotherapy for MBC were randomized to receive nab-paclitaxel 300 mg/m² q3w, nab-paclitaxel 100 mg/m² or 150 mg/m² the first 3 of 4 weeks (qw 3/4), or docetaxel 100 mg/m² q3w. The trial was powered for analyses of antitumor activity and safety.ResultsTreatment with nab-paclitaxel 150 mg/m² qw 3/4 resulted in a median overall survival (OS) of 33.8 months compared with 22.2, 27.7, and 26.6 months for nab-paclitaxel 100 mg/m² qw 3/4, nab-paclitaxel 300 mg/m² q3w, and docetaxel, respectively (overall P = .047). Patients receiving 150 mg/m² nab-paclitaxel had prolonged median OS compared with those in the 100 mg/m² nab-paclitaxel arm (hazard ratio, 0.575; P = .008). A trend toward a longer OS was noted in the 150 mg/m² nab-paclitaxel arm versus docetaxel arm (hazard ratio, 0.688). Grade 3 or 4 fatigue, neutropenia, and febrile neutropenia were less frequent in all nab-paclitaxel arms compared with docetaxel.ConclusionsConsistent with previously published efficacy results, these data suggest that 150 mg/m² qw 3/4 may represent the most clinically efficacious nab-paclitaxel dosing regimen for patients with no previous chemotherapy for MBC. A phase III trial confirming these results would be necessary and prudent before widespread adoption of the 150 mg/m² dose in clinical practice.     

Intermittent versus continuous chemotherapy in advanced colorectal cancer: a randomised ‘GISCAD’ trial

BackgroundIn advanced colorectal cancer, chemotherapy is usually administered without pauses and until progression but patients can experience cumulative toxicity and cannot tolerate a heavy therapeutic charge.AimThe aim of the present trial was to evaluate whether an intermittent chemotherapy with levo-leucovorin + 5-fluorouracil (5-FU) + irinotecan (CPT-11) was at least as effective as the same regimen given continuously, both administered until progression, in patients affected with advanced colorectal cancer and not previously exposed to chemotherapy for metastatic disease.Patients, materials and methodsA total of 337 patients from 27 institutions were randomised between levo-leucovorin, 100/mg/m² i.v. + 5-FU; 400 mg/m² i.v. bolus + 5-FU; 600 mg/m² 22-h continuous infusion, days 1 and 2 + CPT-11; 180 mg/m² day 1, administered every 2 weeks 2 months on and 2 months off (arm A) and the same regimen administered continuously (arm B), until progression in both arms. The main end point was overall survival (OS), the secondary progression-free survival (PFS) and toxicity.ResultsAt a median follow-up of 41 months, OS was 18 months in arm A and 17 months in arm B [hazard ratio (HR), 0.88]. Also PFS was comparable in the two groups (6 months in both, with HR, 1.03), and even grades 3–4 toxicity (mainly myelosuppression, fever and diarrhoea) was similar. Second-line oxaliplatin-based treatment was administered in a similar percentage (66%) in the two arms. The median chemotherapy-free period (drug holiday) in arm A was 3.5 months.ConclusionReducing the charge of therapy in this population did not diminish the efficacy of treatment. Further studies with this strategy, including biologicals, are warranted.     

Chemotherapy (CT) and hormonotherapy (HT) as neoadjuvant treatment in luminal breast cancer patients: results from the GEICAM/2006-03, a multicenter,randomized, phase-II study

BackgroundLuminal breast cancer is a highly endocrine responsive disease. However, the therapeutic benefit of chemotherapy (CT) in this population is not fully characterized. This study investigates the value of CT and hormone therapy (HT) in luminal breast cancer patients in the neoadjuvant setting.Patients and MethodsPatients with operable breast cancer and immunophenotypically defined luminal disease (ER+/PR+/HER2-/cytokeratin 8/18+) were recruited. Patients were randomized to CT (epirubicin 90 mg/m² plus cyclophosphamide 600 mg/m² × 4 cycles followed by docetaxel 100 mg/m² × 4 cycles [EC-T]) or HT (exemestane 25 mg daily × 24 weeks [combined with goserelin in premenopausal patients]). The primary end point was the clinical response measured by magnetic resonance imaging.ResultsNinety-five patients were randomized (47 CT, 48 HT). The clinical response rate was 66% for CT and 48% for HT (P = 0.075). We performed an unplanned analysis based on Ki67 levels (cut-off of 10%). Similar clinical response was seen between arms in patients with low Ki67 (CT: 63%, HT: 58%; P = 0.74); patients with high Ki67 had a better response with CT (67 versus 42%; P = 0.075). Grade 3/4 toxicity was more frequent with CT.ConclusionsLuminal immunophenotype is not enough to identify patients who do not benefit from neoadjuvant CT. Luminal patients with low proliferation index could potentially avoid CT.     

S-1 and Oxaliplatin Versus Tegafur-uracil and Leucovorin as Postoperative Adjuvant Chemotherapy in Patients With High-risk Stage III Colon Cancer (ACTS-CC 02): A Randomized,Open-label,Multicenter, Phase III Superiority Trial

BackgroundThe efficacy of S-1 plus oxaliplatin (SOX) as postoperative adjuvant chemotherapy for colon cancer has not been established. This randomized phase III study was designed to verify the superiority of SOX over tegafur-uracil and leucovorin (UFT/LV) in patients with high-risk stage III colon cancer (any T, N2, or positive nodes around the origin of the feeding arteries).Patients and MethodsPatients who underwent curative resection for pathologically confirmed high-risk stage III colon cancer were randomly assigned to receive either UFT/LV (300 mg/m² of UFT and 75 mg/day of LV on days 1-28, every 35 days, 5 cycles) or SOX (100 mg/m² of oxaliplatin on day 1 and 80 mg/m² of S-1 on days 1-14, every 21 days, 8 cycles). The primary endpoint was disease-free survival (DFS).ResultsA total of 478 patients in the UFT/LV group and 477 patients in the SOX group were included in the primary analysis. The 3-year DFS was 60.6% (95% confidence interval [CI], 56.0%-64.9%) in the UFT/LV group and 62.7% (95% CI, 58.1%-66.9%) in the SOX group. The stratified hazard ratio for DFS was 0.90 (95% CI, 0.74-1.09; stratified log-rank test, P = .2780). In the N2b subgroup, the 3-year DFS was 46.0% (95% CI, 37.5%-54.0%) in the UFT/LV group and 54.7% (95% CI, 45.7%–62.7%) in the SOX group (hazard ratio, 0.76; 95% CI, 0.55-1.05).ConclusionAs postoperative adjuvant chemotherapy, SOX was not superior to UFT/LV in terms of DFS in patients with high-risk stage III colon cancer.     

A phase II feasibility study of palbociclib in combination with adjuvant endocrine therapy for hormone receptor-positive invasive breast carcinoma

BackgroundThe CDK4/6 inhibitor palbociclib prolongs progression-free survival in hormone receptor-positive/HER2-negative (HR+/HER2−) metastatic breast cancer when combined with endocrine therapy. This phase II trial was designed to determine the feasibility of adjuvant palbociclib and endocrine therapy for early breast cancer.Patients and methodsEligible patients with HR+/HER2− stage II–III breast cancer received 2 years of palbociclib at 125 mg daily, 3 weeks on/1 week off, with endocrine therapy. The primary end point was discontinuation from palbociclib due to toxicity, non-adherence, or events related to tolerability. A discontinuation rate of 48% or higher would indicate the treatment duration of 2 years was not feasible, and was evaluated under a binomial test using a one-sided α = 0.025.ResultsOverall, 162 patients initiated palbociclib; over half had stage III disease (52%) and most received prior chemotherapy (80%). A total of 102 patients (63%) completed 2 years of palbociclib; 50 patients discontinued early for protocol-related reasons (31%, 95% CI 24% to 39%, P = 0.001), and 10 discontinued due to protocol-unrelated reasons. The cumulative incidence of protocol-related discontinuation was 21% (95% CI 14% to 27%) at 12 months from start of treatment. Rates of palbociclib-related toxicity were congruent with the metastatic experience, and there were no cases of febrile neutropenia. Ninety-one patients (56%) required at least one dose reduction.ConclusionAdjuvant palbociclib is feasible in early breast cancer, with a high proportion of patients able to complete 2 years of therapy. The safety profile in the adjuvant setting mirrors that observed in metastatic disease, with approximately half of the patients requiring dose-modification. As extended duration adjuvant palbociclib appears feasible and tolerable for most patients, randomized phase III trials are evaluating clinical benefit in this population.Clinicaltrials.gov registrationNCT02040857.     

Cladribine in the Treatment of Acute Myeloid Leukemia: A Single-Institution Experience

BackgroundDespite advances in novel therapeutics, supportive care, and postremission therapy, the outcome of high-risk and elderly patients as well as those with relapsed/refractory acute myeloid leukemia (AML) remains poor. There is likely still room for improvement through optimizing conventional chemotherapy.Patients and MethodsThrough a pharmacy database search we identified all patients with AML treated at Washington University with cladribine-based regimens.ResultsTwenty-four patients were identified that were treated with 2 cladribine-based regimens: CLAG (cladribine [5 mg/m² days 1-5], cytarabine [2 g/m² days 1-5] and granulocyte colony-stimulating factor [G-CSF; 300 μg subcutaneously (s.c.) days 0-5]) and CLAM (cladribine [5 mg/m² days 1-5], cytarabine [2 g/m² days 1-5], G-CSF [300 mg s.c. days 0-5] and mitoxantrone [10 mg/m² days 1-3]). Complete responses were achieved in 53% of patients given induction chemotherapy and 44% of those given salvage chemotherapy. The regimens were well tolerated with minimal extramedullary toxicity.ConclusionThese data suggest that cladrabine-based regimens should be further explored in both the salvage and first-line setting and might offer an attractive backbone on which to add novel therapies.