Anticancer drugs directed against the microtubule, including taxanes and vinca alkaloids, have been the backbone of many chemotherapy regimes for decades. These drugs have, however, significant ...limitations, which have prompted the development of novel microtubule targeting agents (MTAs). This article will discuss MTAs for anticancer therapies and recent debates regarding their mechanisms of action. Furthermore, the limitations of taxanes, including hypersensitivity reactions, neurotoxicity, drug resistance and lack of validated biomarkers to guide therapy will be discussed, all of which have driven the development of novel agents. The mechanisms of action and drug development of new generations of MTAs will also be outlined. Agents demonstrating utility in Phase III clinical trials, including eribulin, ixabepilone, cabazitaxel and trastuzumab-DM1 will be highlighted, as well as novel agents currently in development and future directions for MTAs.
Summary Background Oxaliplatin-based adjuvant therapy is the standard of care for stage III colon cancer. Adjuvant capecitabine with or without oxaliplatin versus leucovorin and fluorouracil with or ...without oxaliplatin has not been directly compared; therefore, we aimed to analyse the efficacy and safety of these treatments using individual patient data pooled from four randomised controlled trials. We also assessed post-relapse survival, which has been postulated to be worse in patients receiving adjuvant oxaliplatin. Methods Patients with resected stage III colon cancer who were 18 years of age or older, with an Eastern Cooperative Oncology Group performance status of 0 or 1, from four randomised controlled trials (NSABP C-08, XELOXA, X-ACT, and AVANT; 8734 patients in total) were pooled and analysed. The treatment regimens included in our analyses were: XELOX (oxaliplatin and capecitabine); leucovorin and fluorouracil; capecitabine; FOLFOX-4 (leucovorin, fluorouracil, and oxaliplatin); and modified FOLFOX-6 (mFOLFOX-6). Disease-free survival was the primary endpoint for all trials that supplied patients for this analysis. Here, we compared disease-free, relapse-free, and overall survival between the patient groups who received capecitabine with or without oxaliplatin and those who received leucovorin and fluorouracil with or without oxaliplatin. Post-relapse survival was compared between the combined XELOX and FOLFOX groups, and the leucovorin and fluorouracil groups. Post-relapse survival was also compared between the capecitabine with or without oxaliplatin and leucovorin and fluorouracil with or without oxaliplatin groups. Findings Disease-free survival did not differ significantly between patients who received leucovorin and fluorouracil versus those who received capecitabine in adjusted analyses (hazard ratio HR 1·02 0·93–1·11; p=0·72) or in unadjusted analyses (HR 1·01 95% CI 0·92–1·10; p=0·86). Relapse-free survival was similar (adjusted HR 1·02 0·93–1·12; p=0·72 and unadjusted HR 1·01 95% CI 0·92–1·11; p=0·86), as was overall survival (adjusted HR 1·04 95% CI 0·93–1·15; p=0·50 and unadjusted HR 1·02 0·92–1·14; p=0·65). For overall survival, a significant interaction between oxaliplatin and fluoropyrimidine was recorded in the multiple Cox regression analysis (p=0·014). Post-relapse survival was similar in adjusted (p=0·23) and unadjusted analyses (p=0·33) for the comparison of XELOX or FOLFOX versus leucovorin and fluorouracil, and was also similar for capecitabine-based regimens versus leucovorin and fluorouracil-based regimens (unadjusted p=0·26). Interpretation Combination therapy with oxaliplatin provided consistently improved outcomes without adversely affecting post-relapse survival in the adjuvant treatment of stage III colon cancer, irrespective of whether the fluoropyrimidine backbone was capecitabine or leucovorin and fluorouracil. These data add to the existing evidence that oxaliplatin plus capecitabine or leucovorin and fluorouracil is the standard of care for the adjuvant treatment of stage III colon cancer, and offers physicians flexibility to treat patients according to the patients' overall physical performance and preference. Funding Genentech Inc.
Summary Background Treatments with survival benefit are greatly needed for women with heavily pretreated metastatic breast cancer. Eribulin mesilate is a non-taxane microtubule dynamics inhibitor ...with a novel mode of action. We aimed to compare overall survival of heavily pretreated patients receiving eribulin versus currently available treatments. Methods In this phase 3 open-label study, women with locally recurrent or metastatic breast cancer were randomly allocated (2:1) to eribulin mesilate (1·4 mg/m2 administered intravenously during 2–5 min on days 1 and 8 of a 21-day cycle) or treatment of physician's choice (TPC). Patients had received between two and five previous chemotherapy regimens (two or more for advanced disease), including an anthracycline and a taxane, unless contraindicated. Randomisation was stratified by geographical region, previous capecitabine treatment, and human epidermal growth factor receptor 2 status. Patients and investigators were not masked to treatment allocation. The primary endpoint was overall survival in the intention-to-treat population. This study is registered at ClinicalTrials.gov , number NCT00388726. Findings 762 women were randomly allocated to treatment groups (508 eribulin, 254 TPC). Overall survival was significantly improved in women assigned to eribulin (median 13·1 months, 95% CI 11·8–14·3) compared with TPC (10·6 months, 9·3–12·5; hazard ratio 0·81, 95% CI 0·66–0·99; p=0·041). The most common adverse events in both groups were asthenia or fatigue (270 54% of 503 patients on eribulin and 98 40% of 247 patients on TPC at all grades) and neutropenia (260 52% patients receiving eribulin and 73 30% of those on TPC at all grades). Peripheral neuropathy was the most common adverse event leading to discontinuation from eribulin, occurring in 24 (5%) of 503 patients. Interpretation Eribulin showed a significant and clinically meaningful improvement in overall survival compared with TPC in women with heavily pretreated metastatic breast cancer. This finding challenges the notion that improved overall survival is an unrealistic expectation during evaluation of new anticancer therapies in the refractory setting. Funding Eisai.
Summary Background Prediction of response to anthracycline-based therapy for breast cancer is challenging. We aimed to assess the value of HER2 and TOP2A as predictive markers of response to ...anthracycline-based adjuvant therapy in patients with early breast cancer. Methods We did a meta-analysis of individual patient data from five randomised adjuvant trials that compared anthracycline-based regimens with cyclophosphamide, methotrexate, and fluorouracil (CMF) regimens. We assessed the status of HER2 and TOP2A genes with fluorescent in-situ hybridisation. Tumour samples were submitted to an external laboratory for validation. We calculated hazard ratios (HR) to compare event-free survival (EFS) and overall survival in patients receiving anthracycline-based treatment with those receiving CMF in two HER2 cohorts ( HER2 amplified and non-amplified tumours) and in three TOP2A cohorts (normal, amplified, and deleted tumours). Findings We analysed data for 3452 patients for HER2 and 3102 patients for TOP2A . For EFS, HRs were 0·89 (95% CI 0·79–1·01) for HER2 non-amplified patients and 0·71 (0·58–0·86) for HER2 -amplified patients (pinteraction =0·0485); for overall survival, HRs were 0·91 (95% CI 0·79–1·05) for HER2 non-amplified patients and 0·73 (0·59–0·89) for HER2 -amplified patients (pinteraction =0·0718). In analysis of TOP2A status, HRs for EFS were 0·88 (0·78–1·00) for normal, 0·63 (0·46–0·87) for deleted, and 0·62 (0·43–0·90) for amplified (pinteraction =0·0513); HRs for overall survival were 0·89 (0·78–1·03) for normal, 0·68 (0·49–0·95) for deleted, and 0·67 (0·46–0·98) for amplified (pinteraction =0·1608). When patients with TOP2A -deleted and TOP2A -amplified tumours were grouped together (altered cohort) and compared with data from patients with normal TOP2A tumours, HRs for EFS were 0·64 (0·50–0·81) for altered and 0·88 (0·78–1·00) for normal (pinteraction =0·0183); HRs for overall survival were 0·67 (0·52–0·86) for altered and 0·89 (0·78–1·03) for normal (pinteraction =0·0455). Interpretation Although HER2 amplification and combined TOP2A amplification and deletion may have some value in the prediction of responsiveness to anthracycline-based chemotherapy, our findings do not support the use of anthracyclines only in patients with HER2 -amplified or TOP2A -aberrated tumours. Funding Associazione Italiana Ricerca Cancro, Academy of Finland, Belgian Federation Against Cancer, Cancer Research UK, Les Amis de l'Institut Bordet, Scottish Breast Cancer Trials Group, NCIC Clinical Trials Group, Canadian Cancer Society Research Institute, Danish Council for Strategic Research, Pharmacia-Upjohn (now Pfizer), and Abbott Laboratories.
Abstract Background Prognostic models have been developed to predict survival of patients with newly diagnosed glioblastoma (GBM). To improve predictions, models should be updated with information at ...the recurrence. We performed a pooled analysis of European Organization for Research and Treatment of Cancer (EORTC) trials on recurrent glioblastoma to validate existing clinical prognostic factors, identify new markers, and derive new predictions for overall survival (OS) and progression free survival (PFS). Methods Data from 300 patients with recurrent GBM recruited in eight phase I or II trials conducted by the EORTC Brain Tumour Group were used to evaluate patient’s age, sex, World Health Organisation (WHO) performance status (PS), presence of neurological deficits, disease history, use of steroids or anti-epileptics and disease characteristics to predict PFS and OS. Prognostic calculators were developed in patients initially treated by chemoradiation with temozolomide. Results Poor PS and more than one target lesion had a significant negative prognostic impact for both PFS and OS. Patients with large tumours measured by the maximum diameter of the largest lesion (⩾42 mm) and treated with steroids at baseline had shorter OS. Tumours with predominant frontal location had better survival. Age and sex did not show independent prognostic values for PFS or OS. Conclusions This analysis confirms performance status but not age as a major prognostic factor for PFS and OS in recurrent GBM. Patients with multiple and large lesions have an increased risk of death. With these data prognostic calculators with confidence intervals for both medians and fixed time probabilities of survival were derived.
Lymphoedema is a recognised complication of axillary surgery in women with early breast cancer. Such women are widely advised to avoid venepuncture on the ipsilateral side lest this cause ...complications including lymphoedema. This can lead to multiple failed venepuncture attempts causing distress to both patient and healthcare professional. We reviewed current guidelines and critically appraised the evidence relating the development of lymphoedema to venepuncture to educate healthcare professionals and develop evidence-based guidelines. A systematic search of bibliographic databases was performed and an Internet search undertaken to identify patient information leaflets from societies and support groups. Seven published articles were identified together with 15 published patient information leaflets. Only one small prospective study was identified (level of evidence 2), the remainder being case–control studies (level 3) or retrospective reviews (level 4). There is no good evidence that venepuncture can precipitate lymphoedema. New, patient-centred, evidence-based recommendations for venepuncture in women with breast cancer are proposed. Whenever possible, venepuncture should be performed on the contralateral arm. If this is not readily achieved, in the absence of lymphoedema it is preferable to consider venepuncture in the ipsilateral arm or insertion of a central venous device than to make further attempts in the contralateral arm or resort to sites such as veins in the foot. In the absence of lymphoedema, venesection in the ipsilateral arm carries little, if any, risk of additional complications. We offer evidence-based, patient-centred guidelines for venepuncture in patients with breast cancer following an axillary intervention.
Summary Background The NEAT/BR9601 trial showed benefit for addition of anthracyclines to cyclophosphamide, methotrexate, and fluorouracil (CMF) as adjuvant treatment for early breast cancer. We ...investigated prospectively predictive biomarkers of anthracycline benefit including HER2 and TOP2A. Methods 1941 tumours from 2391 women recruited to NEAT/BR9601 were analysed on tissue microarrays for HER2 and TOP2A amplification and deletion, HER1–3 and Ki67 expression, and duplication of chromosome 17 centromere enumeration probe (Ch17CEP). Log-rank analyses identified factors affecting relapse-free and overall survival, and regression models tested independent prognostic effect of markers, with adjustment for known prognostic factors (age, nodal status, oestrogen-receptor status, grade, and tumour size). The predictive value of markers was tested by treatment interactions for relapse-free and overall survival. Findings 1762 patients were analysed. 21% of tumours (n=367) were HER2 amplified, 10% were TOP2A amplified (n=169), 11% showed TOP2A deleted (n=191), 23% showed Ch17CEP duplication (n=406), and 61% had high (>13·0%) Ki67 (n=1136). In univariate analyses, only HER2 amplification and TOP2A deletion were significant prognostic factors for relapse-free (hazard ratio HR 1·59, 95% CI 1·32–1·92, p<0·0001; and 1·52, 1·20–1·92, p=0·0006, respectively) and overall survival (1·79, 1·47–2·19, p<0·0001; and 1·62, 1·26–2·08, p=0·0002 respectively). We detected no significant interaction with anthracycline benefit for Ki67, HER2, HER1–3 , or TOP2A . By contrast, in multivariate analyses, Ch17CEP duplication was associated with significant improvements in both relapse-free (HR 0·92, 95% CI 0·72–1·18 for tumours with normal Ch17CEP vs 0·52, 0·34–0·81 for tumours with abnormal Ch17CEP; p for interaction=0·004) and overall survival (0·94, 0·72–1·24 vs 0·57, 0·36–0·92; p for interaction=0·02) with anthracycline use. Interpretation In women with early breast cancer receiving adjuvant chemotherapy, the most powerful predictor of benefit from anthracyclines is Ch17CEP duplication. In view of the location of HER2/TOP2A on chromosome 17, Ch17CEP duplication might explain the inconsistencies in previous studies of factors predicting benefit from anthracyclines. Funding Cancer Research UK and the Scottish Breast Cancer Clinical Trials Group.
The standard combination of intravenous fluorouracil plus leucovorin for adjuvant treatment of colon cancer was compared with the oral fluoropyrimidine capecitabine in almost 2000 patients with ...resected colon cancer. With disease-free survival as the primary end point, capecitabine was at least as effective as fluorouracil plus leucovorin. The oral drug had fewer side effects than the intravenous combination.
With disease-free survival as the primary end point, capecitabine was at least as effective as fluorouracil plus leucovorin. The oral drug had fewer side effects than the intravenous combination.
Almost 1 million patients receive a diagnosis of colorectal cancer yearly, and half a million deaths from this neoplasm occur annually worldwide.
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Each year, approximately 230,000 patients with colon cancer are eligible for adjuvant chemotherapy.
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The benefits of fluorouracil-based adjuvant chemotherapy in reducing the risk of relapse and prolonging survival in patients with resected colon cancer are well established, particularly in stage III disease.
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Survival advantages were demonstrated with bolus intravenous fluorouracil plus leucovorin administered according to the Mayo Clinic regimen (five days, monthly, for six months) or the Roswell Park regimen (weekly bolus, six of every eight . . .
The activity and safety of eribulin mesylate (E7389), a nontaxane microtubule dynamics inhibitor with a novel mechanism of action, were evaluated in patients with locally advanced or metastatic ...breast cancer previously treated with an anthracycline, taxane, and capecitabine.
Eligible patients in this single-arm, open-label phase II study received eribulin mesylate (1.4 mg/m(2)) administered as a 2- to 5-minute intravenous infusion on days 1 and 8 of a 21-day cycle. The primary end point was objective response rate (ORR) assessed by independent review.
Of 299 enrolled patients who had received a median of four prior chemotherapy regimens, 291 received eribulin (for a median of four cycles). Of these, 269 patients met key inclusion criteria for the primary efficacy analysis. The primary end point of ORR by independent review was 9.3% (95% CI, 6.1% to 13.4%; all partial responses PRs), the stable disease (SD) rate was 46.5%, and clinical benefit rate (complete response + PR + SD > or = 6 months) was 17.1%. The investigator-reported ORR was 14.1% (95% CI, 10.2% to 18.9%). Median duration of response was 4.1 months, and progression-free survival was 2.6 months. Median overall survival was 10.4 months. The most common treatment-related grade 3 or 4 toxicities were neutropenia (54%; febrile neutropenia, 5.5%), leukopenia (14%), and asthenia/fatigue (10%; no grade 4); grade 3 neuropathy occurred in 6.9% of patients (no grade 4).
Eribulin demonstrated antitumor activity in extensively pretreated patients who had previously received an anthracycline, taxane, and capecitabine, with a manageable tolerability profile.
Current prognostic tools in colon cancer use relatively few patient characteristics. We constructed and validated clinical calculators for overall survival (OS) and time to recurrence (TTR) for stage ...III colon cancer and compared their performance against an existing tool (Numeracy) and American Joint Committee on Cancer (AJCC) version 7 staging.
Data from 15936 stage III patients accrued to phase III clinical trials since 1989 were used to construct Cox models for TTR and OS. Variables included age, sex, race, body mass index, performance status, tumor grade, tumor stage, ratio of positive lymph nodes to nodes examined, number and location of primary tumors, and adjuvant treatment (fluoropyrimidine single agent or in combination). Missing data were imputed, and final models internally validated for optimism-corrected calibration and discrimination and compared with AJCC. External validation and comparisons against Numeracy were performed using stage III patients from NSABP trial C-08. All statistical tests were two-sided.
All variables were statistically and clinically significant for OS prediction, while age and race did not predict TTR. No meaningful interactions existed. Models for OS and TTR were well calibrated and associated with C-indices of 0.66 and 0.65, respectively, compared with C-indices of 0.58 and 0.59 for AJCC. These tools, available online, better predicted patient outcomes than Numeracy, both overall and within patient subgroups, in external validation.
The proposed ACCENT calculators are internally and externally valid, better discriminate patient risk than AJCC version 7 staging, and better predict patient outcomes than Numeracy. These tools have replaced Numeracy for online clinical use and will aid prognostication and patient/physician communication.
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