Randomised controlled trial of doxorubicin-eluting beads vs conventional chemoembolisation for hepatocellular carcinoma

Background:

Transcatheter arterial chemoembolisation (TACE) is the treatment of choice for intermediate stage hepatocellular carcinoma (HCC). Doxorubicin-loaded drug-eluting beads (DEB)-TACE is expected to improve the performance of conventional TACE (cTACE). The aim of this study was to compare DEB-TACE with cTACE in terms of time-to-tumour progression (TTP), adverse events (AEs), and 2-year survival.

Methods:

Patients were randomised one-to-one to undergo cTACE or DEB-TACE and followed-up for at least 2 years or until death. Transcatheter arterial chemoembolisation was repeated ‘on-demand''.

Results:

We enrolled 177 patients: 89 underwent DEB-TACE and 88 cTACE. The median number of procedures was 2 in each arm, and the in-hospital stay was 3 and 4 days, respectively (P=0.323). No differences were found in local and overall tumour response. The median TTP was 9 months in both arms. The AE incidence and severity did not differ between the arms, except for post-procedural pain, more frequent and severe after cTACE (P<0.001). The 1- and 2-year survival rates were 86.2% and 56.8% after DEB-TACE and 83.5% and 55.4% after cTACE (P=0.949). Eastern Cooperative Oncology Group (ECOG), serum albumin, and tumour number independently predicted survival (P<0.05).

Conclusions:

The DEB-TACE and the cTACE are equally effective and safe, with the only advantage of DEB-TACE being less post-procedural abdominal pain.     

Randomised trial: survival benefit and safety of adjuvant dose-dense chemotherapy for node-positive breast cancer

We evaluated the survival benefit, safety, feasibility, and tolerability of dose-dense (DD) adjuvant chemotherapy with epirubicin and paclitaxel for women with node-positive primary breast cancer. Randomised patients (n=216) received DD or conventional-schedule (CS) chemotherapy. Dose-dense regimen patients (n=108) received epirubicin 90 mg m-2 plus paclitaxel 175 mg m-2 in four 14-day cycles, then cyclophosphamide 600 mg m-2, methotrexate 40 mg m-2, and fluorouracil 600 mg m-2 (CMF 600/40/600) in three 14-day cycles, plus filgrastim 5 microg kg day-1 as growth support in every cycle. Conventional-schedule regimen patients (n=108) received epirubicin 90 mg m-2 plus cyclophosphamide 600 mg m-2 in four 21-day cycles, then CMF 600/40/600 in three 21-day cycles, plus filgrastim if required. After a median follow-up of 38.4 months, 71 patients (33%) relapsed or died: DD, 33 patients (15 deaths); CS, 38 patients (22 deaths). Dose dense showed a trend for improved disease-free survival (DFS) and overall survival (OS). Four-year rates of DFS and OS were 64 and 85% for DD, and 58 and 75% for CS. All seven cycles were administered to 208 patients (96%). Rates of cycle delay, discontinuation, dose reduction, and adverse events were similar in both groups. Dose-dense sequential chemotherapy with epirubicin/paclitaxel then CMF, supported by filgrastim, is safe and improves survival for patients with node-positive breast cancer.     

Randomised controlled trial of breast cancer and multiple disease prevention weight loss programmes vs written advice amongst women attending a breast cancer family history clinic

Background Overweight and obesity are common amongst women attending breast cancer Family History, Risk and Prevention Clinics (FHRPCs). Overweight increases risk of breast cancer (BC) and conditions including¹ cardiovascular disease (CVD) and type-2 diabetes (T2D). Clinics provide written health behaviour advice with is likely to have minimal effects. We assessed efficacy of two remotely delivered weight loss programmes vs. written advice.Method 210 women with overweight or obesity attending three UK FHRPCs were randomised to either a BC prevention programme (BCPP) framed to reduce risk of BC (n = 86), a multiple disease prevention programme (MDPP) framed to reduce risk of BC, CVD and T2D (n = 87), or written advice (n = 37). Change in weight and health behaviours were assessed at 12-months.Results Weight loss at 12 months was −6.3% (−8.2, −4.5) in BCPP, −6.0% (−7.9, −4.2) in MDPP and −3.3% (−6.2, −0.5) in the written group (p = 0.451 across groups). The percentage losing ≥10% weight in these groups were respectively 34%, 23% and 14% (p = 0.038 across groups).Discussion BCPP and MDPP programmes resulted in more women achieving ≥10% weight loss, but no evidence of additional benefits of MDPP. A multicentre RCT to test the BCPP across UK FHRPCs is warranted.Clinical Trial Registration ISRCTN16431108.Subject terms: Weight management, Nutrition     

Randomised trial of SIR-Spheres? plus chemotherapy vs.chemotherapy alone for treating patients with liver metastases fromprimary large bowel cancer

Purpose:SIR-Spheres® are radioactiveyttrium⁹⁰ microspheres (SIR-Spheres®, Sirtex MedicalLimited, Australia) used to selectively target high levels of ionisingradiation to tumors within the liver. This trial was designed to measureany increased patient benefit by adding a single administration ofSIR-Spheres to a regimen of regional hepatic artery chemotherapy (HAC)administered as a 12 day infusion of floxuridine and repeated at monthlyintervals, vs. the same chemotherapy alone. Patients andmethods:A phase III randomised clinical trial entering 74 patientswas undertaken on patients with bi-lobar non-resectable liver metastasesfrom primary adenocarcinoma of the large bowel. Patient benefit criteriaassessed in the trial were tumor response, time to disease progressionin the liver, overall survival, quality of life, and treatment relatedtoxicity. Tumor response was measured by serial changes in bothcross-sectional tumor areas and total tumor volumes, provided anyresponse lasted not less than three months as well as changes in serumcarcino-embryonic antigen (CEA). Results:The partialand complete response rate (PR + CR) was significantly greater forpatients receiving SIR-Spheres when measured by tumor areas (44%vs. 17.6%, P= 0.01) tumor volumes (50% vs.24%, P= 0.03) and CEA (72% vs. 47%, P= 0.004).The median time to disease progression in theliver was significantly longer for patients receiving SIR-Spheres incomparison to patients receiving HAC alone when measured by either tumorareas (9.7 vs. 15.9 months, P= 0.001), tumor volumes (7.6 vs.12.0 months, P= 0.04) or CEA (5.7 vs. 6.7 months, P =0.06).The one, two, three and five-year survival for patientsreceiving SIR-Spheres was 72%, 39%, 17% and3.5%, compared to 68%, 29%, 6.5% and0% for HAC alone. Cox regression analysis suggests an improvementin survival for patients treated with SIR-Spheres who survive more than15 months (P = 0.06). There was no increase in grade 3–4treatment related toxicity and no loss of quality of life for patientsreceiving SIR-Spheres in comparison to patients receiving HAC alone. Conclusion:The combination of a single injection ofSIR-Spheres® plus HAC is substantially more effective in increasingtumor responses and progression free survival than the same regimen ofHAC alone.     

Primary chemotherapy for early breast cancer

The use of primary chemotheraphy represents a novel approach being used with increasing frequency in the management of early breast cancer. Many studies now testify to the usefulness of this modality in increasing the frequency of breast conservation. The acceptance of high-risk breast cancer as a systemic, and therefore predominantly medical rather than a surgical, disease suggests, however, that its role is likely to be far more reaching. While some trials have so far suggested the possibility of a survival benefit for this approach, definitive conclusions are not yet possible and await the final mature results from several large randomized studies. Even if such studies do not show a large extra benefit for primary chemotheraphy over existing adjuvant treatment, the use of the primary tumour as an in vivo model of individual chemosensitivity and the identification of molecular markers as early predictors of response, suggest that this approach will become an integral part of the modern multidisciplinary management of early breast cancer.     

A comparison of intermittent vs. continuous and of adriamycin vs. methotrexate 5-drug chemotherapy for advanced breast cancer. A Cancer and Leukemia Group B study

The therapeutic effectiveness of intermittent vs. continuous combination chemotherapy and of the substitution of adriamycin for methotrexate in a 5-drug regimen was evaluated in women with metastatic breast carcinoma. Patients were randomly allocated to receive continuous therapy with cyclophosphamide, methotrexate, 5-fluorouracil, vincristine, prednisone ( CMFVP -C, 86 patients), intermittent CMFVP ( CMFVP -I, 109 patients), or intermittent CAFVP (107 patients). The CR + PR rate with CAFVP (71%) was superior to CMFVP -C (50%, p = 0.003) and to CMFVP -I (50%, p = 0.002). The remission duration with CAFVP (14 months, median) was superior to CMFVP -I (7 months) (p less than 0.01), and tended to be superior to CMFVP -C (9 months) (p = 0.07). There was a survival advantage of CAFVP (19 months, median) over CMFVP -I (13 months) (p = 0.01), but not over CMFVP -C (16 months) (p = 0.24). Among CR + PR patients, the survival with CAFVP (29 months, median) was superior (p = 0.02) to both CMFVP -I (18 months) and CMFVP -C (21 months). The CMFVP -C regimen was associated with the highest incidence of leukopenia and neurologic toxicity, but the lowest incidence of GI toxicity. The results indicate that the CAFVP regimen is well tolerated and is superior to the CMFVP regimens.     

Metastatic breast cancer: controlled trial of chemotherapy with and without hormones

Two hundred and twenty-three patients with disseminated breast cancer entered in a randomized trial: Group I: 130 patients were given a monthly 5 day- course of a cytotoxic chemotherapy protocol including Adriamycine, Vincristine, Cyclophosphamide, 5 Fluoro-uracile (A.V.L.F.); Group II: 93 patients were given alternatively the same program and a non cross resistant program including: VM 26, Mitomycine C, Methotrexate (V.M.M.). The patients of these groups were randomized into three subgroups: Subgroup O: chemotherapy alone; Subgroup N: chemotherapy + Tamoxifen (20 mg/m2/day); Subgroup NN: chemotherapy + Tamoxifen + Norethisterone (40 mg/m2/day). Objective response rates to cytotoxic chemotherapy were respectively of 65 per cent and 68 per cent in groups I and II of chemotherapy. Further more mean-duration of response and survival were not different. Objective response rates were comparable in the three subgroups of chemo-hormonotherapy. However, the survival was significantly better in the subgroup N (with Tamoxifen) when compared with the subgroup O (without hormonotherapy), and marginally better (p = 0,09) when compared with the NN subgroup (with Tamoxifen + Norethisterone).     

Optimum anthracycline-based chemotherapy for early breast cancer

Adjuvant chemotherapy improves the overall survival of women treated after surgery for early breast cancer. Several trials have suggested that anthracycline-containing regimens are more effective than those that do not contain anthracyclines. A modest overall benefit has also been confirmed by the Early Breast Cancer Trialists' Collaborative Group overview. Newer agents, such as the taxanes, are now being tested in the adjuvant setting in randomised trials. The control group of such studies should receive the optimum standard treatment. There are several anthracycline-based regimens in common use, varying in terms of the type of anthracycline used, the dose, and drug scheduling. We review the available evidence and consider whether the optimum anthracycline-containing chemotherapy schedule has now been identified.     

Randomised controlled trial of a supervised exercise rehabilitation program for colorectal cancer survivors immediately after chemotherapy: study protocol

Background  

Colorectal cancer (CRC) diagnosis and the ensuing treatments can have a substantial impact on the physical and psychological health of survivors. As the number of CRC survivors increases, so too does the need to develop viable rehabilitation programs to help these survivors return to good health as quickly as possible. Exercise has the potential to address many of the adverse effects of CRC treatment; however, to date, the role of exercise in the rehabilitation of cancer patients immediately after the completion of treatment has received limited research attention. This paper presents the design of a randomised controlled trial which will evaluate the feasibility and efficacy of a 12-week supervised aerobic exercise program (ImPACT Program) on the physiological and psychological markers of rehabilitation, in addition to biomarkers of standard haematological outcomes and the IGF axis.     

Six-month follow-up of patient-rated outcomes in a randomized controlled trial of exercise training during breast cancer chemotherapy.

BACKGROUND: Few exercise trials in cancer patients have reported longer-term follow-up. Here, we report a 6-month follow-up of exercise behavior and patient-rated outcomes from an exercise trial in breast cancer patients. METHODS: Breast cancer patients initiating adjuvant chemotherapy (n = 242) were randomly assigned to usual care (n = 82), resistance exercise training (RET; n = 82), or aerobic exercise training (AET; n = 78) for the duration of their chemotherapy. At 6-month follow-up, participants were mailed a questionnaire that assessed quality of life, self-esteem, fatigue, anxiety, depression, and exercise behavior. RESULTS: Two hundred one (83.1%) participants provided 6-month follow-up data. Adjusted linear mixed-model analyses showed that, at 6-month follow-up, the RET group reported higher self-esteem [adjusted mean difference, 1.6; 95% confidence interval (95% CI), 0.1-3.2; P = 0.032] and the AET group reported lower anxiety (adjusted mean difference, -4.7; 95% CI, -0.0 to -9.3; P = 0.049) compared with the usual care group. Moreover, compared with participants reporting no regular exercise during the follow-up period, those reporting regular aerobic and resistance exercise also reported better patient-rated outcomes, including quality of life (adjusted mean difference, 9.5; 95% CI, 1.2-17.8; P = 0.025). CONCLUSIONS: Improvements in self-esteem observed with RET during breast cancer chemotherapy were maintained at 6-month follow-up whereas reductions in anxiety not observed with AET during breast cancer chemotherapy emerged at 6-month follow-up. Moreover, adopting a combined aerobic and resistance exercise program after breast cancer chemotherapy was associated with further improvements in patient-rated outcomes. Exercise training during breast cancer chemotherapy may result in some longer-term and late effects for selected patient-rated outcomes.     

Update on adjuvant chemotherapy for early breast cancer

Adjuvant chemotherapy represents a significant advance in the management of early-stage breast cancer and, as such, has saved many lives. Worldwide, adjuvant chemotherapy has benefitted all groups tested, including pre- and postmenopausal women, those with node-negative and node-positive disease, and those with estrogen-receptor (ER)-positive and ER-negative disease. However, the significant number of women who relapse despite adjuvant therapy provides the impetus to develop more efficacious regimens. Results from large randomized clinical trials, which will mature over the next few years, will clarify the potential benefits of the taxanes in the adjuvant setting, provide answers as to the efficacy of a dose-dense approach, and define a role, if any, for high-dose chemotherapy. A shift toward targeted therapies has also begun, with the incorporation of trastuzumab (Herceptin) into the adjuvant setting. Minimizing the long-term toxicity of adjuvant therapy for the large number of women who survive their disease is paramount. This article highlights the need to develop predictive factors to help tailor individual therapy.     

GnRH agonist for protection against ovarian toxicity during chemotherapy for early breast cancer: the Anglo Celtic Group OPTION trial

BackgroundChemotherapy-induced premature ovarian insufficiency (POI) impacts fertility and other aspects of women’s health. The OPTION trial tested whether administration of a gonadotropin-releasing hormone agonist during chemotherapy for early breast cancer reduced the risk of POI.Patients and methodsThis was a prospective, randomized, parallel group study of the gonadotropin-releasing hormone agonist goserelin administered before and during chemotherapy for breast cancer with stage I–IIIB disease. The primary outcome was amenorrhoea between 12 and 24 months after randomization, supported by elevated follicle stimulating hormone concentrations to give an additional analysis as rate of POI.ResultsA total of 227 patients were randomized and the primary analysis was conducted on 202 patients. Goserelin reduced the prevalence of amenorrhoea between 12 and 24 months to 22% versus 38% in the control group (P = 0.015) and the prevalence of POI to 18.5% versus 34.8% in the control group (P = 0.048). Follicle stimulating hormone concentrations were also lower in all women treated with goserelin at both 12 and 24 months (P = 0.027, P = 0.001, respectively). The effect of goserelin was not statistically significant in women >40 years. Assessment of the ovarian reserve using anti-Müllerian hormone showed a marked fall in both groups during treatment to median values of 5% of pretreatment levels in the control group and 7% in the goserelin group, which were not significantly different between groups.ConclusionThis study shows that goserelin reduced the risk of POI in women treated with chemotherapy for early breast cancer, with particular efficacy in women aged ≤40 years old. The degree of ovarian protection also seems limited and the clinical significance for fertility and longer term prevention of estrogen deficiency-related outcomes needs to be determined.     

A randomized trial of chemotherapy (L-PAM vs CMF) and irradiation for node positive breast cancer

Summary 158 evaluable patients with stage II, lymph node positive, carcinoma of the breast were randomized to adjuvant therapy with either melphalan (L-PAM) or cyclophosphamide, methotrexate, and fluorouracil (CMF) after mastectomy. In addition, patients were randomized to be treated with or without post-operative irradiation therapy (RT) in addition to their chemotherapy. At a median follow-up time of 11 years, there is no difference in time to relapse (P=0.69) or survival (P=0.55) among the four treatment groups. Multivariate analysis including treatment arm, age, race, tumor size, histologic type, performance status, time to onset of treatment, menopausal status, and number of positive nodes, revealed that only the number of positive nodes (<4 vs 4) was related to disease-free and overall survival. Ten year relapse-free survival for patients with <4 positive nodes compared to those with 4 positive nodes was 63% versus 30%, and overall survival 63% versus 41%, respectively. Patients who received post-operative radiation therapy had significantly less local recurrence than those treated with chemotherapy alone (P=0.03) but without improvement in relapse-free or overall survival. In this trial, post-operative radiation therapy when added to chemotherapy decreased the risk of local recurrence without adverse effects on survival. Treatment outcome was not influenced by chemotherapy regimen, but differences may have been obscured by the small sample size.     

Time trends of neoadjuvant chemotherapy for early breast cancer

Neoadjuvant chemotherapy (NACT) in early breast cancer (EBC) enables in vivo sensitivity testing and less radical surgery as compared to primary surgery and adjuvant chemotherapy (ACT). The aim of our study is to illustrate trends of systemic treatment of EBC. The study analyzed chemotherapy usage and time trends for patients with EBC treated at 104 German breast units between January 2008 and December 2017. The data were obtained through a quality-controlled benchmarking process. Altogether, 124 084 patients were included, of whom 46 279 (37.3%) received chemotherapy. For 44 765 of these cases, detailed information on systemic treatment and surgery were available. Overall use of chemotherapy declined from 42.0% in 2008 to 32.0% in 2017. During that same time, the proportion of NACT increased from 20.0% to 57.7%, irrespective of tumor subtype. The pathological complete response (pCR) rate (defined as ypT0 ypN0) at surgery after NACT increased from 15.0% to 34.2%. The results from this large cohort from the clinical routine reflect the refined indications for chemotherapy in EBC.     

Randomised phase II trial of gemcitabine plus vinorelbine vs gemcitabine plus cisplatin vs gemcitabine plus capecitabine in patients with pretreated metastatic breast cancer

Background:

An increasing proportion of patients are exposed to anthracyclines and/or taxanes in the adjuvant or neoadjuvant setting. Re-exposure in the metastatic stage is limited by drug resistance, thus evaluation of non-cross-resistant regimens is mandatory.

Methods:

Anthracycline-pretreated patients were randomly assigned to three gemcitabine-based regimens. Chemotherapy consisted of gemcitabine 1.000 mg m⁻² plus vinorelbin 25 mg m⁻² on days 1+8 (GemVin), or plus cisplatin 30 mg m⁻² on days 1+8 (GemCis), or plus capecitabine 650 mg m⁻² b.i.d. orally days 1–14 (GemCap), q3w. The primary end point was response rate.

Results:

A total of 141 patients were recruited on the trial. The overall response rates were 39.0% (GemVin), 47.7% (GemCis) and 34.7% (GemCap). Median progression-free survival was estimated with 5.7, 6.9 and 8.3 months, respectively. Corresponding median survival times were 17.5 (GemVin), 13.0 (GemCis) and 19.4 months (GemCap). Neutropenia ⩾grade 3 occurred in 16.7% (Gem/Vin), 4.4% (GemCis) and 0% (Gem/Cap), whereas non-haematological toxicities were rarely severe except grade 3 hand–foot syndrome in 2.0% of the GemCap patients (per patient analysis).

Conclusions:

This randomised phase II trial has revealed comparable results for three gemcitabine-based regimens regarding treatment efficacy and toxicity. Gemcitabine-based chemotherapy appears to be a worthwhile treatment option for pretreated patients with metastatic breast cancer.