Adjuvant bisphosphonates improve disease outcomes in postmenopausal early breast cancer (EBC) but the long-term effects are poorly described. The AZURE trial (ISRCTN79831382) was designed to determine whether adjuvant zoledronic acid (ZOL) improves disease outcomes in EBC. Previous analyses showed no effect on overall outcomes but identified benefits in postmenopausal women. Here we present the long-term risks and benefits of adjuvant ZOL with 10-years follow-up. Patients and methods: 3360 patients with stage II/III breast cancer were included in an academic, international, phase III, randomized, open label trial. Patients were followed up on a regular schedule until 10 years. Patients were randomized on a 1: 1 basis to standard adjuvant systemic therapy +/- intravenous ZOL 4 mg every 3-4 weeks x6, and then at reduced frequency to complete 5 years treatment. The primary outcome was disease free survival (DFS). Secondary outcomes included invasive DFS (IDFS), overall survival (OS), sites of recurrence, skeletal morbidity and treatment outcomes according to primary tumor amplification of the transcription factor, MAF. Pre-planned subgroup analyses focused on interactions between menopausal status and treatment effects. Results: With a median follow up of 117 months [IQR 70.4-120.4), DFS and IDFS were similar in both arms (HRDFS=0.94, 95% CI=0.84-1.06, p=0.340; HRIDFS=0.91, 95% CI=0.82-1.02, p=0.116). However, outcomes remain improved with ZOL in postmenopausal women (HRDFS=0.82, 95% CI=0.67-1.00; HRIDFS=0.78, 95% CI=0.64-0.94). In the 79% of tested women with a MAF FISH negative tumor, ZOL improved IDFS (HRIDFS=0.75, 95% CI=0.58-0.97) and OS HROS=0.69, 95% CI=0.50-0.94), irrespective of menopause. ZOL did not improve disease outcomes in MAF FISH+ tumors. Bone metastases as a first DFS recurrence (BDFS) were reduced with ZOL (HRB-DFS=0.76, 95% CI=0.63-0.92, p=0.005). ZOL reduced skeletal morbidity with fewer fractures and skeletal events after disease recurrence. 30 cases of osteonecrosis of the jaw in the ZOL arm (1.8%) have occurred. Conclusions: Disease benefits with adjuvant ZOL in postmenopausal early breast cancer persist at 10 years of follow-up. The biomarker MAF identified a patient subgroup that derived benefit from ZOL irrespective of menopausal status.

ABSTRACT Background TURANDOT is the first prospective trial to compare BEV combined with either paclitaxel (PAC) or capecitabine (CAP). We report the planned interim analysis (IA) of efficacy. Methods Patients with HER2-negative mBC who had received no prior chemotherapy for mBC were randomised to receive either BEV–PAC (BEV 10 mg/kg d1 & 15 + PAC 90 mg/m d1, 8 & 15 q4w) or BEV–CAP (BEV 15 mg/kg d1 + CAP 1000 mg/m bid d1–14 q3w) until disease progression or unacceptable toxicity. The primary objective is to demonstrate non-inferior overall survival (OS) with BEV–CAP vs BEV–PAC. Interim and final OS analyses were planned after 175 and 389 deaths, respectively, in the per-protocol (PP) population to reject the null hypothesis of inferiority (hazard ratio [HR] ≥1.33) with 80% power and overall α = 0.025. Secondary endpoints include response rate (RR), progression-free survival (PFS), safety and quality of life. Results Median follow-up was 19 months at data cut-off for this IA (1 Sep 2011). Baseline characteristics were generally similar in the 2 treatment arms. BEV-PAC (n = 285) BEV–CAP (n = 279) Median age, years 59 59 Visceral metastases, % 65 73 Prior (neo)adjuvant taxane, % 20 18 OS a Events, % 33 35 1-year OS rate, % b 81 79 HR (97.5% RCI c ) for non-inferiority 1.04 (-∞ to 1.69) p = 0.0593 d RR Overall, % 44 27 CMH test (superiority) p  PFS Events, % 62 77 Median, months 11.0 8.1 HR (95% CI) 1.36 (1.09 to 1.68) Log-rank (superiority) p = 0.0052 RCI = repeated confidence interval a PP population (n = 533) b Kaplan–Meier estimate c Using O'Brien–Fleming boundaries d Non-inferiority not shown as p > 0.00105 (α at IA) AEs were consistent with the known safety profiles of BEV, PAC and CAP. The most common grade ≥3 AEs were neutropenia (18%), peripheral neuropathy (14%) and leucopenia (7%) with BEV–PAC and hand-foot syndrome (16%), hypertension (6%) and diarrhoea (5%) with BEV–CAP. Conclusion In this planned IA, the non-inferiority criterion has not been met but OS results do not indicate relevant differences. Final results are expected in 2014. PFS and RR were better with BEV–PAC and very similar to previous data for BEV–PAC (E2100) and BEV–CAP (RIBBON-1). Disclosure R. Greil: RG has received research support and honoraria from Roche. S. Beslija: SB has received research support and honoraria from Roche. D. Messinger: Employee of IST GmbH, CRO which is providing various services and consultancies for Hoffmann-La Roche and CECOG. T. Brodowicz: TB has received honoraria from Roche. All other authors have declared no conflicts of interest.

ABSTRACT Background Abiraterone irreversibly inhibits 17-hydroxylase/c-17-20 lyase (CYP17), reducing androgen and estrogen levels and improves overall survival from castration resistant prostate cancer. We hypothesized that: A) Postmenopausal ERα+ MBC continue to be ERα + /AR driven; and, B) Postmenopausal ERα- AR+ MBC can be driven by AR. Methods This Phase I/II trial of AA with hydrocortisone evaluated tolerability, pharmacokinetic (PK)-pharmacodynamic (PD) profile and anti-tumor activity. Two parallel but non-randomized Phase II arms utilized a Gehan design (95% probability of detecting a 24wk clinical benefit rate (CBR, partial response [PR] + stable disease) of > 20%; 14 patients [pts] in the first stage; 11 in the second stage for each arm). Prior therapy with ≥ 2 lines of endocrine therapy (for ERα+ arm); ≥ 1 line of chemo (for AR + ERα- arm); and prior trastuzumab if HER2-positive was required. ERα and AR positivity was defined as immunoreactivity in ≥ 1% cells. Results In the phase I study, daily dosing of AA was well tolerated with variable PK at all dose levels. PD studies of CYP17 blockade demonstrated suppression of circulating estradiol and androgen levels below the limit of assay detection with 1000mg and 250-2000mg AA respectively; 1000mg was selected for Phase II evaluation. In the ERα+ arm, 6 pts (Phase I) and 25pts (Phase II) received 1000mg AA, of whom 4 were HER2-positive. The median age (range) was 60 (46-80), prior lines of hormonal and chemotherapy were 3 (2-4) and 2 (0-5) respectively. There was 1 partial response (PR) lasting 14m in a pt who had received 4 and 5 lines of hormonal and chemotherapy respectively. Median progression-free survival was 11wk. CBR at 24wk was 21%. In the AR + ERα- arm, recruitment is ongoing. Hypokalaemia easily managed by hydrocortisone administration, was the commonest drug related adverse event (AE). Conclusion AA was well tolerated and merits further evaluation in MBC. Cancer Research UK (Drug Development Office) Sponsored and funded the trial. Johnson & Johnson provided AA. Disclosure M. Dowsett: The Institute of Cancer Research has a commercial interest in Abiraterone. Mitch Dowsett is an employee of the Institute of Cancer Research, which has a ‘Rewards to Inventors’ scheme and is a recipient of the scheme. J.S. de Bono: The Institute of Cancer Research has a commercial interest in Abiraterone. Prof de Bono is an employee of the Institute of Cancer Research, and recipient of a ‘Rewards to Inventors’ scheme. He is also a consultant for Johnson and Johnson. All other authors have declared no conflicts of interest.

Abstract Introduction: TACT2, a multicentre phase III trial with E-CMF as control (NEAT Poole NEJM 2006), tests 2 hypotheses in a 2x2 factorial design: A) accelerating chemotherapy (CT) offers superior benefits (CALGB9741 Citron JCO 2003); B) the oral 5FU prodrug capecitabine (X) gives similar efficacy but preferential side-effect profile to CMF. Here, focus is on hypothesis A with results for compliance, QL and acute toxicities (physician & patient (pt) reported) during E vs aE. Materials & Methods: Dec 2005-08 4391 pts (4371 women, 20 men) with node +ve or high risk node -ve invasive EBC were recruited. Pts were randomised to receive either E (100mg/m2 x 4) q3wk or q2wk aE (100mg/m2 x 4 plus pegfilgrastim, 6mg d2) followed by classical CMF q4wk x 4 or X (2500mg/m2/day x 14) q3wk x 4. Detailed CTCAE toxicity was to be assessed in subset (38 centres, 2137 pts). Of these, 2127 pts received ≥1 cycle CT. 1279 of these pts completed pt-reported outcomes (EORTC QLQ-C30 and pre-defined pt-reported TACT2 toxicities) with 910 completing baseline on time and having end cycle 4 data. P<0.01 classed as significant. Toxicities/which differ between groups are shown where p-values are trend tests across all grades & % grade 3+ are reported. QL assessed via linear regression models. Results: 33/4391 pts did not start CT. 4259 (97%) completed the initial 4 cycles (E 2143 (96%), aE 2116 (98%) with RDI >85% for E 2058 (93%) and aE 1983 (91%). During cycles 1-4 higher rates of hand-foot syndrome & anaemia were seen with aE vs E (P<0.001). Few were grade 3+ (E 0%, aE 0.9% & E 0%, aE 0.1%) respectively. Lower grade 3+ rates (all P<0.001) were seen with aE vs E for: ANY toxicity (E 27%, aE 18%), leucopenia (E 4%, aE 1%), neutropenia (E 17%, aE 2%) & febrile neutropenia (E 4%, aE 2%). Change from baseline in global QL, role functioning & fatigue was worse with aE vs E (P<0.001); no differences were reported for aE vs E for impact of individual pre-defined TACT2 toxicities on daily activities (Nausea, vomiting, tingling hands and/or feet, diarrhoea, constipation, sore mouth, mouth ulcers). Conclusion: In TACT2, the largest adjuvant trial reporting acute toxicities for standard vs accelerated E in EBC, serious CTCAE toxicity was less common with aE compared with E, however pts report poorer global QL, fatigue & role function which does not appear to be explained by impact on daily activities due to individual side-effects. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-10-06.

PURPOSE OF INVESTIGATIONTo evaluate the prognostic significance for overall survival rate for the marker combination TPS and CA125 in ovarian cancer patients after three chemotherapy courses during long-term clinical follow-up.METHODSThe overall survival of 212 (out of 213) ovarian cancer patients (FIGO Stages I-IV) was analyzed in a prospective multicenter study during a 10-year clinical follow-up by univariate and multivariate analysis.RESULTSIn patients with ovarian cancer FIGO Stage I (34 patients) or FIGO Stage II (30 patients) disease, the univariate and multivariate analysis of the 10-year overall survival data showed that CA125 and TPS serum levels were not independent prognostic factors. In the FIGO Stage III group (112 patients), the 10-year overall survival was 15.2%; while in the FIGO Stage IV group (36 patients) a 10-year overall survival of 5.6% was seen. Here, the tumor markers CA125 and TPS levels were significant prognostic factors in both univariate and multivariate analysis (p < 0.0001). In a combined FIGO Stage III + FIGO Stage IV group (60 patients with optimal debulking surgery), multivariate analysis demonstrated that CA125 and TPS levels were independent prognostic factors. For patients in this combined FIGO Stage III + IV group having both markers below respective discrimination level, 35.3% survived for more than ten years, as opposed to patients having one marker above the discrimination level where the 10-year survival was reduced to 10% of the patients. For patients showing both markers above the respective discrimination level, none of the patients survived for the 10-year follow-up time.CONCLUSIONIn FIGO III and IV ovarian cancer patients, only patients with CA 125 and TPS markers below the discrimination level after three chemotherapy courses indicated a favorable prognosis. Patients with an elevated level of CA 125 or TPS or both markers after three chemotherapy courses showed unfavorable prognosis.

tAnGo is a large randomised trial assessing the addition of gemcitabine(G) to paclitaxel(T), following epirubicin(E) and cyclophosphamide(C) in women with invasive higher risk early breast cancer. To assess the safety and tolerability of adding G, a detailed safety substudy was undertaken. A total of 135 patients had cardiac, pulmonary and hepatic function assessed at (i) randomisation, (ii) mid-chemotherapy, (iii) immediately post-chemotherapy and (iv) 6 months post-chemotherapy. Skin toxicity was assessed during radiotherapy. No differences were detected in FEV(1) or FVC levels between treatment arms or time points. Diffusion capacity (TL(CO)) reduced during treatment (P<0.0001), with a significantly lower drop in EC-GT patients (P=0.02). Most of the reduction occurred during EC and recovered by 6-months post treatment. There was no difference in cardiac function between treatment arms. Only 11 patients had echocardiography/MUGA results change from normal to abnormal during treatment, with only five having LVEF<50%. Transient transaminitis occurred in both treatment arms with significantly more in EC-GT patients post-chemotherapy (AST P=0.03, ALT P=0.003), although the majority was low grade. There was no correlation between transaminitis and other toxicities. Both treatment regimens reported temporary reductions in pulmonary functions and transient transaminitis levels. Despite these being greater with EC-GT, both regimens appear well tolerated.

AIM:The TELEMAM trial aimed to assess the clinical effectiveness and costs of telemedicine in conducting breast cancer multi-disciplinary meetings (MDTs).METHODS:Over 12 months 473 MDT patient discussions in two district general hospitals (DGHs) were cluster randomised (2:1) to the intervention of telemedicine linkage to breast specialists in a cancer centre or to the control group of 'in-person' meetings. Primary endpoints were clinical effectiveness and costs. Economic analysis was based on a cost-minimisation approach.RESULTS:Levels of agreement of MDT members on a scale from 1 to 5 were high and similar in both the telemedicine and standard meetings for decision sharing (4.04 versus 4.17), consensus (4.06 versus 4.20) and confidence in the decision (4.16 versus 4.07). The threshold at which the telemedicine meetings became cheaper than standard MDTs was approximately 40 meetings per year.CONCLUSION:Telemedicine delivered breast cancer multi-disciplinary meetings have similar clinical effectiveness to standard 'in-person' meetings.

LBA1005 Background: Phase II studies of weekly paclitaxel (P) confirm this to be a well tolerated regimen in ABC with potentially superior efficacy to standard q3w schedules. This was tested in the phase III CALGB 9840 trial, which used a “patient resource conserving” design, combining randomised patients with imported control data from a previous CALGB study of predominantly 2nd line treatment. This and the higher total dose of P in the weekly arm, left many unsure if there really was superior activity for the weekly schedule. Methods: The primary efficacy objective was to detect a 2 month improvement (6 to 8 months, HR = 1.33) in time to progression (TTP) by the giving the same total dose of P weekly (wP) vs. 3 weekly (3wP). 560 randomised patients were required to give 90% power to detect this difference at the 0.05 significance level. A single analysis was planned six months after study closure. Secondary endpoints include overall survival, toxicity and quality of life. The primary translational endpoint is a pharmacogenetic (PG) study of the effect of MDR and CYP single nucleotide polymorphisms. Between Sept. 2002 and July 2006, 569 patients were randomized to receive either wP 90 mg/m2 for 12 weeks or 3wP 175 mg/m2 for 6 cycles. Patients were stratified for measurable disease, prior treatment for ABC and Trastuzumab use. Results: The investigator reported response rates were 27% (3wP) and 42% (wP), p=0.002. Median TTP was 22.0 weeks for 3wP (95% CI 19.7–24.6) and 23.9 weeks for wP (95% CI 20.7–26.7), HR=0.92, p=0.06. Both schedules were well tolerated. PG samples from 325 patients are being matched to the unblinded efficacy data. Conclusions: This phase III trial shows that, for a matched total dose, wP produces a higher response rate than 3wP. This confirms the result from CALGB 9840. The mismatch in treatment duration in this trial may explain why TTP with wP was superior in CALGB 9840 while in the current study we have failed to detect superiority despite a higher response rate. Combining the trial results supports the hypothesis that total dose and schedule of P are important. Our results support the widespread adoption of wP as the standard schedule. No significant financial relationships to disclose.

Exemestane is a potent steroidal aromatase inhibitor (AI) with activity in post-menopausal women with metastatic breast cancer, with a reported clinical benefit (CB) rate of 24.3% after prior AI therapy. Data on 114 patients (112 female, 2 male) were obtained retrospectively at two cancer centres. Sixty-five percent of patients were confirmed as oestrogen receptor (ER) positive. All patients had received prior third-generation AI therapy. Responses were seen in 5% and the overall CB rate (CR+PR+SD⩾24 weeks) was 46%. Median PFS and OS were 18 and 61 weeks, respectively. In patients with visceral disease, the CBR was 33%. Patients with known ER-positive disease had a CBR of 47%, and a median TTP of 19 weeks. No benefit was seen in patients with known ER-negative disease. Survival was better in those with CB (median survival not reached in those with CB, 28 weeks in those without CB P < 0.0001 ). Efficacy persisted in those patients who had received ⩾3 prior lines of hormonal therapy, including adjuvant treatment. These data confirm exemestane to be an effective therapy after third-generation non-steroidal AI in post-menopausal ER-positive metastatic breast cancer, including visceral disease.

We surveyed the attitudes of breast cancer professionals to standard face-to-face and future telemedicine-delivered breast multidisciplinary team (MDT) meetings. Interviews, which included the Group Behaviour Inventory, were conducted face-to-face (n= 19) or by telephone (n= 26). The mean total score on the Group Behaviour Inventory was 96 (SD 19) for 33 respondents, which indicated satisfaction with standard MDT meetings, irrespective of role and base hospital. Positive attitudes to videoconferencing were more common among participants with previous experience of telemedicine (Spearman's rank correlation 0.26, P = 0.91). Common themes emerging from the interviews about telemedicine-delivered MDTs included group leadership, meeting efficiency, group interaction, group atmosphere and technical quality of communication. Most participants were satisfied with standard breast MDTs. Nurses and allied health professionals were least supportive of telemedicine.

Multidisciplinary team (MDT) meetings for decisions on cancer management are a cornerstone of UK cancer policy. We have proposed a comprehensive methodology to assess the clinical and economic effectiveness of telemedicine in this setting, which is being tested in a randomized breast cancer trial. Pre- and post-telemedicine assessment includes attitudes to and expectations of telemedicine, based on semistructured interviews. The communication content of videotapes of the MDT meeting is being scored using Borgatta's revised Interaction Process Analysis System. The technical performance of the telemedicine equipment is reported on a standardized pro forma. A short questionnaire captures key elements of professional satisfaction for each patient discussion (consensus on future management, confidence in and sharing of decision), added value of linkage, group atmosphere, overall conduct of the meeting and compliance with SIGN guidelines. A cost-minimization analysis will be used for economic assessment.

Yondelis (ET-743) is a novel anticancer agent isolated from the marine ascidian Ecteinascidia turbinata. ET-743 possesses potent antitumour activity and a novel mechanism of action at the level of gene transcription. We conducted two sequential phase I dose escalation and pharmacokinetic studies of ET-743 given as a 1- or a 3-h intravenous (i.v.) infusion. Seventy-two adults with metastatic or advanced solid tumours received ET-743 in escalating doses between 50 and 1100 microg/m(2), initially as a 1-h infusion, and later at doses between 1000 and 1800 microg/m(2) as a 3-h infusion every 3 weeks. The maximum tolerated dose (MTD) of ET-743 was 1100 microg/m(2) for the 1-h infusion schedule and 1800 microg/m(2) when given as a 3-h infusion. Dose-limiting toxicities (DLTs) were fatigue, neutropenia and thrombocytopenia. Transient non-cumulatives grade 3-4 increase in transaminases (not considered DLT) and grades 3-4 nausea and vomiting were frequently observed. Other toxicities (maximum grade 3) included anaemia, increased lactate dehydrogenase (LDH), bilirubin and alkaline phosphatase serum levels, and phlebitis; there were no toxic deaths. One pCR (melanoma), CR (uterine leiomyosarcoma), one PR (colon stromal sarcoma) and a MR (37% tumour shrinkage, gastric stromal sarcoma) were observed. A further 9 patients with colorectal, mesothelioma, bile duct carcinoma and bladder cancer had SD which lasted for six or more treatment cycles. ET-743 pharmacokinetics were linear with the 3-h infusion schedule. The haematological and hepatic toxicities of ET-743 were dose-dependent and not cumulative. Based on the current trial, the recommended dose of ET-743 for phase II studies is 1650 microg/m(2) given as a 3-h infusion.

Ecteinascidin 743 (ET-743) is an anticancer agent derived from the Caribbean tunicate Ecteinascidia turbinata. In the present article, the pharmacokinetics and pharmacodynamics of ET-743 are described within a phase I study. Forty patients with solid tumors initially received ET-743 as a 1-h i.v. infusion every 21 days at nine dose levels (50-1100 microg/m(2)). The maximal tolerated dose (MTD) was 1100 microg/m(2), with thrombocytopenia and fatigue as dose-limiting toxicities (DLTs). As this MTD was substantially lower than in parallel phase I studies, dose escalation continued using a prolonged, 3-h infusion. Thirty-two patients were entered at five dose levels (1000-1800 microg/m(2)). The MTD was 1800 microg/m(2) with pancytopenia and fatigue as DLTs. The recommended phase II dose was 1650 microg/m(2) given over 3 h at which 12 patients were treated. Pharmacokinetic monitoring was performed for both treatment schedules. Non-compartmental pharmacokinetic parameters at the recommended dose with the 3-h infusion were (mean value+/-SD): clearance 87+/-30 l/h and mean elimination half-life 26+/-7 h. Pharmacokinetics were linear at the dose range tested with this schedule. The percentage decrease in platelets, white blood cells and neutrophils correlated with the area under the plasma concentration versus time curve (AUC), dose and maximal plasma concentration (C(max)). Hepatic toxicity increased with dose, AUC and C(max). Administration of 1650 microg/m(2) ET-743 over 3 h seemed clinically feasible; pharmacokinetics were linear with this schedule. Hepatic and hematological toxicities correlated with exposure to ET-743.

PURPOSE:This study was an open-label Phase II trial of the aromatase inhibitor letrozole (Femara) in patients with relapsed ovarian cancer with evaluation of possible biological markers for response.EXPERIMENTAL DESIGN:60 patients were treated with letrozole (2.5 mg daily) at the time of CA125 relapse. Disease response was assessed by Union International Contre Cancer (UICC) criteria and by CA125 measurement. Estrogen receptor (ER), progesterone receptor, epidermal growth factor receptor, erbB2, and HSP27 were measured by immunohistochemistry in paraffin-fixed material obtained from the primary tumors at initial surgery.RESULTS:50 patients were evaluable by UICC criteria, and although no complete or partial responses were obtained, 10 patients had stable disease on scan for at least 12 weeks. CA125 responses were evaluable in 54 patients. A partial marker response (>50% decrease) was seen in 5, and the marker remained stable in an additional 14 patients (25% increase). Tumors from the UICC stable disease group had significantly higher ER (P = 0.027) and progesterone receptor (P = 0.0066) values than the progressive disease group, and a combination of these was strongly associated with stable disease (P < 0.0001). Using CA125 criteria, comparison of the CA125 stable/responding disease with progressive disease indicated that tumors with higher ER (P = 0.013), lower erbB2 (P = 0.026), and higher epidermal growth factor receptor (P = 0.009) were associated with CA125 stable/responsive disease.CONCLUSIONS:These results imply that letrozole treatment can produce disease stabilization and CA125 responses that in turn are linked to higher levels of ER expression. These data suggest the presence of an endocrine-sensitive group that could be targeted in future studies.

PVI 5FU gives increased response rates and reduced toxicity when compared to bolus 5FU (J Clin Oncol 1989, 425–432). PVI 5FU administration was reported to give highly variable (>1000-fold) plasma 5FU concentrations at steady state (FU Css) which correlated with toxicity (Ann Oncol 1996, 47–53); but only 19 patients were studied. Therefore, we performed a study of PVI 5FU in 61 patients with advanced colorectal cancer to assess the variability (inter- and intra-subject) in 5FU Css associated with PVI 5FU (300 mg m−2 day−1) and to attempt to correlate pharmacodynamic end-points (anti-tumour activity, toxicity) with 5FU Css as a prelude to ‘exposure-guided’ 5FU administration. All 5FU sampling was performed between 10 am and noon. PVI 5FU administration continued to 26 weeks in patients with disease improvement or stabilization. The response rate was 26% (33% stable disease) and median survival was 11 months. Hand–foot syndrome was the most common dose limiting toxicity. Variability in 5FU300Css was considerably less than previously reported; 94 ± 25 ng ml−1(CV = 27%). No relationships were demonstrated between subject mean 5FU300Css and PD end-points such as response, mucositis, diarrhoea and hand–foot syndrome. The lack of correlation suggests that measurement of 5FU concentrations should not be used to individualize dosing in patients receiving PVI 5FU for advanced colorectal cancer. © 2001 Cancer Research Campaign

PURPOSE:This phase I/II study was performed to evaluate the feasibility of administering the topoisomerase inhibitor topotecan in combination with carboplatin.PATIENTS AND METHODS:Topotecan was given as a 30-minute infusion daily for 5 days, with carboplatin given immediately after topotecan on day 5. Treatment was repeated every 21 days. Carboplatin and then topotecan were escalated in sequential cohorts of three to six patients. Four dosage combinations of topotecan days 1 to 5 and carboplatin (day 5) were tested: 0.5 mg/m(2)/d and carboplatin area under the curve (AUC) of 4, topotecan 0.5 mg/m(2)/d and carboplatin AUC of 5, topotecan 0.75 mg/m(2)/d and carboplatin AUC of 5, and topotecan 1.0 mg/m(2)/d and carboplatin AUC of 5.RESULTS:Grade 3 and 4 neutropenia was common at doses of 0.75 mg/m(2)/d and above, but dose-limiting hematologic toxicity occurred in only one patient. The most common reason for dose reduction or delay was failure of myelosuppression to resolve by day 21. Nonhematologic toxicity was generally mild. The maximum-tolerated dose as defined in the protocol was not reached, but topotecan dose escalation was stopped at 1.0 mg/m(2)/d, because delayed neutrophil recovery precluded re-treatment on a 21-day schedule.CONCLUSION:Hematologic toxicity was common but rarely serious, and the combination of topotecan with carboplatin on this schedule was safe and well tolerated. Giving carboplatin to patients after topotecan on day 5, rather than on day 1, allowed dose escalation beyond the levels reported in other studies. The recommended doses for previously treated patients are topotecan 0.75 mg/m(2)/d, days 1 to 5, with carboplatin at an area under the curve (AUC) of 5 following topotecan on day 5. The combination of topotecan 1 mg/m(2)/d, days 1 to 5, followed on day 5 by carboplatin at an AUC of 5, merits further examination in untreated patients.