Dihydropyrimidine dehydrogenase gene variants for predicting grade 4-5 fluoropyrimidine-induced toxicity: FUSAFE individual patient data meta-analysis.

BACKGROUND: Dihydropyrimidine dehydrogenase (DPD) deficiency is the main known cause of life-threatening fluoropyrimidine (FP)-induced toxicities. We conducted a meta-analysis on individual patient data to assess the contribution of deleterious DPYD variants *2A/D949V/*13/HapB3 (recommended by EMA) and clinical factors, for predicting G4-5 toxicity. METHODS: Study eligibility criteria included recruitment of Caucasian patients without DPD-based FP-dose adjustment. Main endpoint was 12-week haematological or digestive G4-5 toxicity. The value of DPYD variants *2A/p.D949V/*13 merged, HapB3, and MIR27A rs895819 was evaluated using multivariable logistic models (AUC). RESULTS: Among 25 eligible studies, complete clinical variables and primary endpoint were available in 15 studies (8733 patients). Twelve-week G4-5 toxicity prevalence was 7.3% (641 events). The clinical model included age, sex, body mass index, schedule of FP-administration, concomitant anticancer drugs. Adding *2A/p.D949V/*13 variants (at least one allele, prevalence 2.2%, OR 9.5 [95%CI 6.7-13.5]) significantly improved the model (p < 0.0001). The addition of HapB3 (prevalence 4.0%, 98.6% heterozygous), in spite of significant association with toxicity (OR 1.8 [95%CI 1.2-2.7]), did not improve the model. MIR27A rs895819 was not associated with toxicity, irrespective of DPYD variants. CONCLUSIONS: FUSAFE meta-analysis highlights the major relevance of DPYD *2A/p.D949V/*13 combined with clinical variables to identify patients at risk of very severe FP-related toxicity.

Multi-omic features of oesophageal adenocarcinoma in patients treated with preoperative neoadjuvant therapy.

Oesophageal adenocarcinoma is a poor prognosis cancer and the molecular features underpinning response to treatment remain unclear. We investigate whole genome, transcriptomic and methylation data from 115 oesophageal adenocarcinoma patients mostly from the DOCTOR phase II clinical trial (Australian New Zealand Clinical Trials Registry-ACTRN12609000665235), with exploratory analysis pre-specified in the study protocol of the trial. We report genomic features associated with poorer overall survival, such as the APOBEC mutational and RS3-like rearrangement signatures. We also show that positron emission tomography non-responders have more sub-clonal genomic copy number alterations. Transcriptomic analysis categorises patients into four immune clusters correlated with survival. The immune suppressed cluster is associated with worse survival, enriched with myeloid-derived cells, and an epithelial-mesenchymal transition signature. The immune hot cluster is associated with better survival, enriched with lymphocytes, myeloid-derived cells, and an immune signature including CCL5, CD8A, and NKG7. The immune clusters highlight patients who may respond to immunotherapy and thus may guide future clinical trials.

SPAR - a randomised, placebo-controlled phase II trial of simvastatin in addition to standard chemotherapy and radiation in preoperative treatment for rectal cancer: an AGITG clinical trial.

BACKGROUND: Retrospective studies show improved outcomes in colorectal cancer patients if taking statins, including overall survival, pathological response of rectal cancer to preoperative chemoradiotherapy (pCRT), and reduced acute and late toxicities of pelvic radiation. Major tumour regression following pCRT has strong prognostic significance and can be assessed in vivo using MRI-based tumour regression grading (mrTRG) or after surgery using pathological TRG (pathTRG). METHODS: A double-blind phase 2 trial will randomise 222 patients planned to receive long-course fluoropyrimidine-based pCRT for rectal adenocarcinoma at 18+ sites in New Zealand and Australia. Patients will receive simvastatin 40 mg or placebo daily for 90 days starting 1 week prior to standard pCRT. Pelvic MRI 6 weeks after pCRT will assess mrTRG grading prior to surgery. The primary objective is rates of favourable (grades 1-2) mrTRG following pCRT with simvastatin compared to placebo, considering mrTRG in 4 ordered categories (1, 2, 3, 4-5). Secondary objectives include comparison of: rates of favourable pathTRG in resected tumours; incidence of toxicity; compliance with intended pCRT and trial medication; proportion of patients undergoing surgical resection; cancer outcomes and pathological scores for radiation colitis. Tertiary objectives include: association between mrTRG and pathTRG grouping; inter-observer agreement on mrTRG scoring and pathTRG scoring; studies of T-cell infiltrates in diagnostic biopsies and irradiated resected normal and malignant tissue; and the effect of simvastatin on markers of systemic inflammation (modified Glasgow prognostic score and the neutrophil-lymphocyte ratio). Trial recruitment commenced April 2018. DISCUSSION: When completed this study will be able to observe meaningful differences in measurable tumour outcome parameters and/or toxicity from simvastatin. A positive result will require a larger RCT to confirm and validate the merit of statins in the preoperative management of rectal cancer. Such a finding could also lead to studies of statins in conjunction with chemoradiation in a range of other malignancies, as well as further exploration of possible mechanisms of action and interaction of statins with both radiation and chemotherapy. The translational substudies undertaken with this trial will provisionally explore some of these possible mechanisms, and the tissue and data can be made available for further investigations. TRIAL REGISTRATION: ANZ Clinical Trials Register ACTRN12617001087347. (www.anzctr.org.au, registered 26/7/2017) Protocol Version: 1.1 (June 2017).

Dose intensity in anthracycline-based chemotherapy for metastatic breast cancer: mature results of the randomised clinical trial ANZ 9311.

PURPOSE: The separate impacts of dose and dose intensity of chemotherapy for metastatic breast cancer remain uncertain. The primary objective of this trial was to compare a short, high-dose, intensive course of epirubicin and cyclophosphamide (EC) with a longer conventional dose regimen delivering the same total dose of chemotherapy. METHODS: This open label trial randomised 235 women with metastatic breast cancer to receive either high-dose epirubicin 150 mg/m2 and cyclophosphamide 1500 mg/m2 with filgrastim support every 3 weeks for 3 cycles (HDEC) or standard dose epirubicin 75 mg/m2 and cyclophosphamide 750 mg/m2 every 3 weeks for 6 cycles (SDEC). Primary outcomes were time to progression, overall survival and quality of life. RESULTS: In 118 patients allocated HDEC 90% of the planned dose was delivered, compared to 96% in the 117 participants allocated SDEC. There were no significant differences in the time to disease progression (5.7 vs. 5.8 months, P = 0.19) or overall survival (14.5 vs. 16.5 months, P = 0.29) between HDEC and SDEC, respectively. Patients on HDEC reported worse quality of life during therapy, but scores improved after completion to approximate those reported by patients allocated SDEC. Objective tumour response was recorded in 33 (28%) on HDEC and 42 patients (36%) on SDEC. HDEC produced more haematologic toxicity. CONCLUSION: For women with metastatic breast cancer, disease progression, survival or quality of life were no better with high-dose intensity compared to standard dose EC chemotherapy. Australian Clinical Trials Registry registration number ACTRN12605000478617.

First-in-human phase I study of infusional and bolus schedules of Deflexifol, a novel 5-fluorouracil and leucovorin formulation, after failure of standard treatment.

BACKGROUND: 5-Fluorouracil (5-FU) is administered with leucovorin (LV) to enhance clinical activity. However, simultaneous administration is not feasible due to their chemical incompatibility, so conditions for the maximum possible beneficial interaction cannot be met. To overcome this, we developed a novel all-in-one, pH neutral stable solution of 5-FU plus LV with ß-cyclodextrin (termed Deflexifol) and assessed its safety and tolerability in a first-in-human phase I trial. METHODS: Patients with advanced solid malignancy received Deflexifol as weekly bolus (375-575 mg/m²) or two-weekly 46 h infusion (1200-3600 mg/m²) for six cycles in a 3+3 dose escalation design. Adverse events, pharmacokinetics and tumor response rates were assessed by standard methods. RESULTS: Forty patients were treated (19 bolus, 21 infusional, median age 67) with no grade 4 adverse events reported. Dose-limiting toxicities of grade 3 diarrhea and myelosuppression were reported for the bolus schedule at 575 mg/m2 (maximum tolerated dose 525 mg/m²), whereas none were reported for the infusional schedule. The recommended phase II infusional dose was declared as 3,000 mg/m², >25% that of 5-FU used in standard-of-care regimens. Pharmacokinetic analyses showed evidence of inter-patient variability, with no evidence of saturation in clearance, and a trend to linear increase in AUC with dose. Disease control rate was 64% despite most patients having failed previous 5-FU regimens. CONCLUSION: Deflexifol is safer and effective in bolus and infusion schedules at higher doses than that permitted by separate infusion of 5-FU and LV. A phase II study evaluating Deflexifol is planned.

Collaborative Patient-Centered Quality Improvement: A Cross-Sectional Survey Comparing the Types and Numbers of Quality Initiatives Selected by Patients and Health Professionals.

Identification of patients' and health professionals' quality improvement preferences is an essential first step in collaborative improvement models. This includes experience-based codesign (EBCD), where service change is strategically introduced following stakeholder consultation. This study compared the number and types of improvement initiatives selected by outpatients and health professionals. Using electronic surveys designed to inform EBCD studies, 541 outpatients (71.1% consent) and 124 professionals (47.1% response) selected up to 23 general initiatives. On average, outpatients selected 2.4 (median = 1, interquartile range = 1-3) initiatives and professionals selected 10.7 (median = 10; interquartile range = 6-15) initiatives. Outpatients demonstrated a strong preference for improvements to clinic organization, such as appointment scheduling and clinic contact. Outpatients selected relatively fewer initiatives potentially reducing the complexity of service change and resources required to address preferences. Comparatively, professionals indicated a greater degree of change is needed and selected initiatives related to communication with patients and other professionals, including coordinating multidisciplinary care. Improvements to information provision were commonly selected by both groups and offered a strategic opportunity to address patients' and professionals' preferences. By quantifying the ways in which preferences differed, this study emphasizes the need for collaborative approaches to health service change and may be used to initiate an informed discussion on patients' and professionals' quality improvement preferences in tertiary care.

The impact on health-related quality of life in the first 12 months: A randomised comparison of preoperative short-course radiation versus long-course chemoradiation for T3 rectal cancer (Trans-Tasman Radiation Oncology Group Trial 01.04).

PURPOSE: To assess health-related quality of life (HRQOL) in patients participating in a randomised trial of neoadjuvant short course radiation (SC) or long course chemoradiation (LC) for operable rectal cancer. PATIENTS AND METHODS: Eligible patients with T3N0-2M0 rectal cancer completed the European Organisation for Research and Treatment of Cancer quality of life questionnaire (QLQ-C30) and the colorectal cancer specific module (QLQ C38) at randomisation and 1, 2, 3, 6, 9 and 12 months later. RESULTS: Of 326 patients randomised, 297 (SC 143, LC 154) were eligible for completion of HRQOL questionnaires. Baseline scores were comparable across the SC and LC groups. Patients reported low scores on sexual functioning and sexual enjoyment. Defaecation problems were the worst of the symptoms at baseline. Surgery had the most profoundly negative effect on HRQOL, seen in both the SC and LC treatment groups to the same extent. The most severely affected domains were physical function and role function and the most severely affected symptoms were fatigue, pain, appetite, weight loss and male sexual problems. Most domains and symptoms returned to baseline levels by 12 months apart from body image, sexual enjoyment and male sexual problems. Future perspective was better than prior to treatment. CONCLUSION: There is no overall difference in HRQOL between SC and LC neoadjuvant treatment strategies, in the first 12 months, after surgery. In the immediate postoperative period HRQOL was adversely affected in both groups but for the most part was temporary. Some residual sexual functioning concerns persisted at 12 months.

Oncology patients overwhelmingly support tissue banking.

BACKGROUND: Translational biomedical research relies on the availability of human tissue to explore disease aetiology and prognostic factors, with the objective of developing better targeted treatments. The establishment of biobanks poses ongoing ethical considerations in relation to donors. This is a quantitative study exploring medical oncology patients' preferences for contributing to tissue biobanks. METHODS: The objectives of this study were to explore oncology patients' preferences about tissue banking, including: 1) willingness to donate; 2) factors influencing donation decisions; 3) preferences about the use of donated tissue including permission systems, data linkage, and communication about research findings to donors. A cross-sectional survey was conducted in two tertiary oncology outpatient clinics. Eligible patients were approached by volunteers to complete a touchscreen survey in waiting rooms or while receiving intravenous therapy. Consenting participants completed demographic questions and received up to 12 previously validated items exploring preferences for donating tissue. RESULTS: 224 oncology outpatients participated over a ten month period (69.1 % consent rate; 64.4 % completion rate). Most participants were female (54 %), were a mean age of 62 years, and diagnosed with breast (26 %) and bowel (20 %) cancer. Most participants indicated willingness to donate tissue (84 %) and for their sample to be stored for future use (96 %). Participants preferred a blanket consent approach (71 %), samples to be linked to medical records (62 %) and for general results of the research (79 %) to be provided to them. Factors influencing willingness to donate tissue included personal (85 %) or familial health benefits (88 %) and a sense of duty to future patients (82 %). CONCLUSIONS: The overwhelming majority of oncology patients are willing to participate in a tissue bank, providing some support to explore 'opt-out' models of consent. To enhance patient acceptability, tissue banking programs should: (i) consider allowing blanket informed consent as well as opt-in models of consent; (ii) develop protocols allowing feedback of information about samples in line with patient preferences; (iii) provide clear information to potential donors about the benefits arising from donation.

Current opinion on optimal treatment for colorectal cancer.

The medical treatment of colorectal cancer (CRC) has evolved greatly in the last 10 years, involving complex combined chemotherapy protocols and, in more recent times, new biologic agents. Advances in adjuvant therapy have been limited to the addition of oxaliplatin and the substitution of oral fluoropyrimidine (e.g., capecitabine) for intravenous 5-fluorouracil with no evidence for improved outcome with biological agents. Clinical benefit from the use of the targeted monoclonal antibodies, bevacizumab, cetuximab and panitumumab, in the treatment of metastatic CRC is now well established, but the optimal timing of their use requires careful consideration to derive the maximal benefit. Evidence to date suggests potentially distinct roles for bevacizumab and EGF receptor-targeted biological agents (cetuximab and panitumumab) in the treatment of metastatic CRC. This article reviews the evidence in support of modern treatments for CRC and the decision-making behind the treatment choices, their benefits and toxicities.

Randomized trial of short-course radiotherapy versus long-course chemoradiation comparing rates of local recurrence in patients with T3 rectal cancer: Trans-Tasman Radiation Oncology Group trial 01.04.

PURPOSE: To compare the local recurrence (LR) rate between short-course (SC) and long-course (LC) neoadjuvant radiotherapy for rectal cancer. PATIENTS AND METHODS: Eligible patients had ultrasound- or magnetic resonance imaging-staged T3N0-2M0 rectal adenocarcinoma within 12 cm from anal verge. SC consisted of pelvic radiotherapy 5 × 5 Gy in 1 week, early surgery, and six courses of adjuvant chemotherapy. LC was 50.4 Gy, 1.8 Gy/fraction, in 5.5 weeks, with continuous infusional fluorouracil 225 mg/m(2) per day, surgery in 4 to 6 weeks, and four courses of chemotherapy. RESULTS: Three hundred twenty-six patients were randomly assigned; 163 patients to SC and 163 to LC. Median potential follow-up time was 5.9 years (range, 3.0 to 7.8 years). Three-year LR rates (cumulative incidence) were 7.5% for SC and 4.4% for LC (difference, 3.1%; 95% CI, -2.1 to 8.3; P = .24). For distal tumors (< 5 cm), six of 48 SC patients and one of 31 LC patients experienced local recurrence (P = .21). Five-year distant recurrence rates were 27% for SC and 30% for LC (log-rank P = 0.92; hazard ratio [HR] for LC:SC, 1.04; 95% CI, 0.69 to 1.56). Overall survival rates at 5 years were 74% for SC and 70% for LC (log-rank P = 0.62; HR, 1.12; 95% CI, 0.76 to 1.67). Late toxicity rates were not substantially different (Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer G3-4: SC, 5.8%; LC, 8.2%; P = .53). CONCLUSION: Three-year LR rates between SC and LC were not statistically significantly different; the CI for the difference is consistent with either no clinically important difference or differences in favor of LC. LC may be more effective in reducing LR for distal tumors. No differences in rates of distant recurrence, relapse-free survival, overall survival, or late toxicity were detected.

Capecitabine versus classical cyclophosphamide, methotrexate, and fluorouracil as first-line chemotherapy for advanced breast cancer.

PURPOSE: We compared oral capecitabine, administered intermittently or continuously, versus classical cyclophosphamide, methotrexate, and fluorouracil (CMF) as first-line chemotherapy for women with advanced breast cancer unsuited to more intensive regimens. PATIENTS AND METHODS: Three hundred twenty-three eligible women were randomly assigned to capecitabine administered intermittently (1,000 mg/m(2) twice daily for 14 of every 21 days; n = 107) or continuously (650 mg/m(2) twice daily for 21 of every 21 days; n = 107), or to classical CMF (oral cyclophosphamide 100 mg/m(2) days 1 to 14 with intravenous methotrexate 40 mg/m(2) and fluorouracil 600 mg/m(2) on days 1 and 8 every 28 days; n = 109). The primary end point was quality-adjusted progression-free survival (PFS); secondary end points included PFS, overall survival (OS), objective tumor response, and adverse events. Intermittent and continuous capecitabine were to be compared first and, if similar (P > .05), combined for definitive comparisons versus CMF. RESULTS: Quality-adjusted PFS (P = .2), objective tumor response rate (20%; P = .8), and PFS (median, 6 months; hazard ratio [HR], 0.86; 95% CI, 0.67 to 1.10; P = .2) were similar in women assigned capecitabine versus CMF. OS was longer in women assigned capecitabine rather than CMF (median, 22 v 18 months; HR, 0.72; 95% CI, 0.55 to 0.94; P = .02). Febrile neutropenia, infection, stomatitis, and serious adverse events were more common with CMF; hand-foot syndrome was more common with capecitabine. CONCLUSION: Capecitabine improved OS by being similarly active, less toxic, and more tolerable than CMF. Capecitabine is a good first-line chemotherapy option for women with advanced breast cancer who are unsuited to more intensive regimens.

A simple HPLC method for plasma level monitoring of mitotane and its two main metabolites in adrenocortical cancer patients.

Mitotane (o,p'-DDD or (1,1-dichloro-2-[o-chlorophenyl]-2-[p-chlorophenyl]ethane, DDD) is the drug of choice for non-resectable and metastatic adrenocortical carcinomas (ACC). Measurement of mitotane and metabolites, o,p'-DDE (1,1-dichloro-2-[p-chlorophenyl]-2-[o-chlorophenyl]ethene, DDE) and o,p'-DDA (1,1-[o,p'-dichlorodiphenyl] acetic acid, DDA) provides a better understanding of mitotane pharmacokinetics and pharmacodynamics. We have developed a simple, robust and efficient high performance liquid chromatography (HPLC) method to measure mitotane and its two main metabolites, DDE and DDA. The method involves a single ethanol extraction of mitotane, DDE, DDA, and an internal standard (int std) p,p'-DDD (1,1-dichloro-2,2-bis(p-chlorophenyl)ethane) with an extraction efficiency of 77-88%. All compounds are measured simultaneously using a reversed-phase phenyl HPLC column with an isocratic elution of mobile phase at a flow rate of 0.6 ml/min followed by UV detection at λ 226 nm. Inter and intra-day validation demonstrates good reproducibility and accuracy. Limits of quantitation are 0.2 µg/ml for mitotane and DDE, and 0.5 µg/ml for DDA. The method has been evaluated in plasma from 23 patients on mitotane therapy, revealing DDA concentrations 1-18 times higher than the parent compound.

Fixed-dose-rate gemcitabine combined with cisplatin in patients with inoperable biliary tract carcinomas.

BACKGROUND: Biliary tract cancers (BTC) have a poor prognosis, and there is no consensus on the best chemotherapy regimen. This study determined the response rate for fixed-dose-rate (FDR) gemcitabine combined with cisplatin. METHODS: This multicentre phase II trial enrolled 50 patients with inoperable locally advanced or metastatic BTC. Treatment consisted of FDR gemcitabine 1,000 mg/m² (10 mg/m²/min) and cisplatin 20 mg/m² on days 1 and 8 of a 21-day cycle. The primary endpoint was response rate. Secondary endpoints included safety, response duration (RD), progression-free (PFS) and overall survival (OS), and cancer antigen 19-9 response. RESULTS: Thirteen patients (26%, 95% CI 14.6-40.4) had a partial response, and 12 (24%) had stable disease. The median RD was 8.3 months (95% CI 6.91-9.99); median PFS 4 months (95% CI 2.5-6.77); and median OS 6.8 months (95% CI 5.0-8.7). Treatment was well tolerated. Grade 3 and grade 4 nausea, vomiting, and fatigue were uncommon. Thirty-eight per cent of patients discontinued treatment because of toxicity, patient or clinician preference. CONCLUSIONS: This treatment combination had moderate activity with acceptable toxicity, supporting previous results that this combination has a role to play. The study does not suggest that FDR gemcitabine is superior to bolus infusion.

Pyridoxine to protect from oxaliplatin-induced neurotoxicity without compromising antitumour effect.

PURPOSE: Oxaliplatin (OHP) in combination with 5-fluorouracil/leucovorin (FOLFOX) is clinically used as frontline therapy in patients with advanced colorectal carcinoma (CRC), with response rates ranging from 46 to 71%. This combination is now considered a standard treatment for metastatic CRC and also in the post-operative adjuvant setting. Reversible, cumulative, peripheral sensory neuropathy is the principal dose-limiting toxicity of OHP therapy. Pyridoxine (vitamin B6) has been shown to reduce cisplatin and fluoropyrimidine-related neurotoxicity but its administration with OHP has not yet been studied. Low doses of pyridoxine are free of side effects; it can be given orally. If pyridoxine administration with oxaliplatin has no adverse effect on OHP cytotoxicity effects, it will be a simple and cost-effective way to minimise OHP-induced neurotoxicity. METHODS: In vitro simultaneous combination of OHP and pyridoxine was studied in 6 CRC cell lines (HT29, Widr, SW480, HCT116, H630 and SW1116), in an ovarian cancer cell line (A2780) and its cisplatin-resistant subline (ADDP) and in an oestrogen-dependent breast cancer cell line (MCF-7). Three fixed concentrations of pyridoxine: 1, 10 and 25 µM were combined with varying concentrations of OHP, and the growth inhibitory effects were evaluated using the MTT cell growth assay. RESULTS: Oxaliplatin induced consistent cytotoxicity in all cell lines with GI(50) values between 0.23 and 7.6 µM. Addition of pyridoxine at concentrations of 1-25 µM does not affect OHP cytotoxicity. CONCLUSIONS: Administration of pyridoxine, at concentrations extending across possible therapeutic plasma levels in humans, does not antagonise OHP antitumour effects in a range of relevant tumour cell lines. This study provides a foundation for clinical studies to test whether pyridoxine can minimise OHP-related neurotoxicity, and clinicians can be confident that pyridoxine is very unlikely to reverse the antitumour effects of OHP, as seems to be the case with Ca/Mg infusions. This could prove to be a cost-effective way to minimise OHP-related neurotoxicity, allowing more effective less toxic treatment and better outcomes in patients.

Capecitabine, bevacizumab, and mitomycin in first-line treatment of metastatic colorectal cancer: results of the Australasian Gastrointestinal Trials Group Randomized Phase III MAX Study.

PURPOSE: To determine whether adding bevacizumab, with or without mitomycin, to capecitabine monotherapy improves progression-free survival (PFS) in patients with metastatic colorectal cancer (mCRC) in an open-label, three-arm randomized trial. PATIENTS AND METHODS: Overall, 471 patients in Australia, New Zealand, and the United Kingdom with previously untreated, unresectable mCRC were randomly assigned to the following: capecitabine; capecitabine plus bevacizumab (CB); or capecitabine, bevacizumab, and mitomycin (CBM). We compared CB with capecitabine and CBM with capecitabine for progression-free survival (PFS). Secondary end points included overall survival (OS), toxicity, response rate (RR), and quality of life (QOL). RESULTS: Median PFS was 5.7 months for capecitabine, 8.5 months for CB, and 8.4 months for CBM (capecitabine v CB: hazard ratio [HR], 0.63; 95% CI, 0.50 to 0.79; P < .001; C v CBM: HR, 0.59; 95% CI, 0.47 to 0.75; P < .001). After a median follow-up of 31 months, median OS was 18.9 months for capecitabine and was 16.4 months for CBM; these data were not significantly different. Toxicity rates were acceptable, and all treatment regimens well tolerated. Bevacizumab toxicities were similar to those in previous studies. Measures of overall QOL were similar in all groups. CONCLUSION: Adding bevacizumab to capecitabine, with or without mitomycin, significantly improves PFS without major additional toxicity or impairment of QOL.

Norcantharidin analogues: synthesis, anticancer activity and protein phosphatase 1 and 2A inhibition.

Cantharidin (1) and its derivatives are of significant interest as serine/threonine protein phosphatase 1 and 2A inhibitors. Additionally, compounds of this type have displayed growth inhibition of various tumour cell lines. To further explore both of these inhibition pathways, a number of amide-acid norcantharidin analogues (15-26) were prepared. Compounds 23 and 24, containing two carboxylic acid residues, showed good PP1 and PP2A activity, with IC(50) values of approximately 15 and approximately 3 mum, respectively. Substituted aromatic amide analogues 45, 48, 49, 52, 53, and 54 also displayed good PP1 and PP2A inhibition, with IC(50) values in the range of 15-10 microM (PP1) and 11-5 microM (PP2A). However, bulky ortho substituents on the aromatic ring caused the aromatic ring to be skewed from the NCO planarity, leading to a decrease in PP1 and PP2A inhibition. A number of analogues, 20, 22, 25 and 46, showed excellent tumour growth inhibition, with 46 in particular being more potent than the lead, norcantharidin 2.

Synthesis and biological evaluation of norcantharidin analogues: towards PP1 selectivity.

Simple modifications to the anhydride moiety of norcantharidin have lead to the development of a series of analogues displaying modest PP1 inhibition (low muM IC(50)s) comparable to that of norcantharidin (PP1 IC(50)=10.3+/-1.37 microM). However, unlike norcantharidin, which is a potent inhibitor of PP2A (IC(50)=2.69+/-1.37 microM), these analogues show reduced PP2A inhibitory action resulting in the development of selective PP1 inhibitory compounds. Data indicates that the introduction of two ortho-disposed substituents on an aromatic ring, or para-substituent favours PP1 inhibition over PP2A inhibition. Introduction of a p-morphilinoaniline substituent, 35, affords an inhibitor displaying PP1 IC(50)=6.5+/-2.3 microM; and PP2A IC(50)=7.9+/-0.82 microM (PP1/PP2A=0.82); and a 2,4,6-trimethylaniline, 23, displaying PP1 IC(50)=48+/-9; and PP2A IC(5) 85+/-3 microM (PP1/PP2A=0.56). The latter shows a 7-fold improvement in PP1 versus PP2A selectivity when compared with norcantharidin. Subsequent analysis of 23 and 35 as potential PP2B inhibitors revealed modest inhibition with IC(50)s of 89+/-6 and 42+/-3 microM, respectively, and returned with PP1/PP2B selectivities of 0.54 and 0.15. Thus, these analogues are the simplest and most selective PP1 inhibitors retaining potency reported to date.

Norcantharimides, synthesis and anticancer activity: Synthesis of new norcantharidin analogues and their anticancer evaluation.

A range of amines was reacted with norcantharidin (2) to provide the corresponding norcantharimides (9-43). Treatment of norcantharidin with allylamine afforded the corresponding allyl-norcantharimide (20) which was amenable to epoxidation (mCPBA, 22) and subsequent ring opening (MeOH/H(+); 23) or alternatively, osmylation (OsO(4)/NMO; 24). These simple synthetic modifications of 2 facilitated the development of a novel series of norcantharimides displaying modest to good broad spectrum cytotoxicity against HT29 and SW480 (colorectal carcinoma); MCF-7 (breast adenocarcinoma); A2780 (ovarian carcinoma); H460 (lung carcinoma); A431 (epidermoid carcinoma); DU145 (prostate carcinoma); BE2-C (neuroblastoma); and SJ-G2 (glioblastoma). Analogues possessing a C(10), C(12) or C(14) alkyl chain or a C(12) linked bis-norcantharimide displayed the highest levels of cytotoxicity.