Disease-free and overall survival at 3.5 years for neoadjuvant bevacizumab added to docetaxel followed by fluorouracil,epirubicin and cyclophosphamide,for women with HER2 negative early breast cancer: ARTemis Trial

BackgroundThe ARTemis trial previously reported that addition of neoadjuvant bevacizumab (Bev) to docetaxel (D) followed by fluorouracil, epirubicin and cyclophosphamide (D-FEC) in HER2 negative breast cancer improved the pathological complete response (pCR) rate. We present disease-free survival (DFS) and overall survival (OS) with central pathology review.Patients and methodsPatients were randomized to 3 cycles of D followed by 3 cycles of FEC (D-FEC), ±4 cycles of Bev (Bev + D-FEC). DFS and OS were analyzed by treatment and by central pathology reviewed pCR and Residual Cancer Burden (RCB) class.ResultsA total of 800 patients were randomized [median follow-up 3.5 years (IQR 3.2–4.4)]. DFS and OS were similar across treatment arms [DFS hazard ratio (HR)=1.18 (95% CI 0.89–1.57), P = 0.25; OS HR = 1.26 (95% CI 0.90–1.76), P = 0.19). Both local pathology report review and central histopathology review confirmed a significant improvement in DFS and OS for patients who achieved a pCR [DFS HR = 0.38 (95% CI 0.23–0.63), P < 0.001; OS HR = 0.43 (95% CI 0.24–0.75), P = 0.003]. However, significant heterogeneity was observed (P = 0.02); larger improvements in DFS were obtained with a pCR achieved with D-FEC than a pCR achieved with Bev + D-FEC. As RCB class increased, significantly worse DFS and OS was observed (P for trend <0.0001), which effect was most marked in the ER negative group.ConclusionsThe addition of short course neoadjuvant Bev to standard chemotherapy did not demonstrate a DFS or OS benefit. Achieving a pCR with D-FEC is associated with improved DFS and OS but not when pCR is achieved with Bev + D-FEC. At the present time therefore, Bev is not recommended in early breast cancer.ClinicalTrials.gov numberNCT01093235.     

The choice of a neoadjuvant chemotherapy cycle for breast cancer has significance in clinical practice: results from a population-based,real world study

Objective: Neoadjuvant chemotherapy(NAC) is currently used in both early stage and locally advanced breast cancers. The survival benefits of standard vs. non-standard NAC cycles are still unclear. This study aimed to investigate the relationship between NAC cycles and survival based on real world data.Methods: We identified patients diagnosed with invasive primary breast cancers who underwent NAC followed by surgery. Patients who received at least 4 NAC cycles were defined as having received sta...     

Is initial excision of cutaneous melanoma by General Practitioners (GPs) dangerous? Comparing patient outcomes following excision of melanoma by GPs or in hospital using national datasets and meta-analysis

BackgroundMelanomas are initially excised in primary care, and rates vary internationally. Until now, there has been no strong evidence one way or the other that excising melanomas in primary care is safe or unsafe. European guidelines make no recommendations, and the United Kingdom (UK) melanoma guidelines require all suspicious skin lesions to be initially treated in secondary care based on an expert consensus, which lacks supporting evidence, that primary care excision represents substandard care. Despite this, studies have found that up to 20% of melanomas in the UK are excised by general practitioners (GPs). Patients receiving primary care melanoma excision may fear that their care is substandard and their long-term survival threatened, neither of which may be justified.MethodsScottish cancer registry data from 9367 people diagnosed with melanoma in Scotland between 2005 and 2013 were linked to pathology records, hospital data and death records. A Cox proportional hazards regression analysis, adjusting for key confounders, explored the association between morbidity and mortality and setting of primary melanoma excision (primary versus secondary care). A pooled estimate of the relative hazard of death of having a melanoma excised in primary versus secondary care including 7116 patients from a similar Irish study was also performed.ResultsThe adjusted hazard ratio (95% CI) of death from melanoma for those having primary care excision was 0.82 (0.61–1.10). Those receiving primary care excision had a median (IQR) of 8 (3–14) out-patient attendances compared to 10 (4–17) for the secondary care group with an adjusted relative risk (RR) (95% CI) of 0.98 (0.96–1.01). Both groups had a median of 1 (0–2) hospital admissions with an adjusted rate ratio of 1.05 (0.98–1.13). In the meta-analysis, with primary care as the reference, the pooled adjusted hazard ratio (HR, 95% CI) was 1.26 (1.07–1.50) indicating a significantly higher all-cause mortality among those with excision in secondary care.ConclusionsThe results of the Scottish and pooled analyses suggest that those receiving an initial excision for melanoma in primary care do not have poorer survival or increased morbidity compared to those being initially treated in secondary care. A randomised controlled trial to inform a greater role for GPs in the initial excision of melanoma is justified in the light of these results.     

A systematic review and meta-analysis on the impact of pre-operative neutrophil lymphocyte ratio on long term outcomes after curative intent resection of solid tumours

IntroductionThere is increasing evidence to suggest that cancer-associated inflammation is associated with poorer long-term outcomes. Various markers have been studied over the past decade in an attempt to improve selection of patients for surgery. This meta-analysis explored the association between the neutrophil-lymphocyte ratio and prognosis following curative-intent surgery for solid tumours.MethodsStudies were identified from US National Library of Medicine (Medline) and the Exerpta Medica database (EBASE) performed in March 2013. A systematic review and meta-analysis were performed to generate combined hazard ratios for overall survival (OS) and disease-free survival (DFS).ResultsForty-nine studies containing 14282 patients were included. Elevated NLR was associated with poorer overall survival [HR: 1.92, 95% CI (1.64–2.24)] (p < 0.001) and disease-free survival [HR: 1.99, 95% CI (1.80–2.20)] (p < 0.001). Significant heterogeneity was found with an I² of 77% and 97% for OS and DFS respectively. Subgroup analyses demonstrated that gastro-intestinal malignancies; mainly gastric [HR: 1.97, 95% CI (1.41–2.76)], colorectal [HR: 1.65, 95% CI (1.21–2.26)] and oesophageal [HR: 1.48, 95% CI (0.91–2.42)] cancers were predictive of OS (I² = 54.3%). A separate analysis for studies using an NLR cutoff of 5 demonstrated significantly poorer outcomes [HR: 2.18, 95% CI (1.74–2.73)] (p = 0.002) with less heterogeneity (I² = 58%).ConclusionElevated NLR correlates with poorer prognosis. It potentially represents a simple, robust and reliable measure that may be useful in identifying high-risk groups who could benefit from adjuvant therapy.     

Neoadjuvant rectal score as individual-level surrogate for disease-free survival in rectal cancer in the CAO/ARO/AIO-04 randomized phase III trial

BackgroundSurrogate end points in rectal cancer after preoperative chemoradiation are lacking as their statistical validation poses major challenges, including confirmation based on large phase III trials. We examined the prognostic role and individual-level surrogacy of neoadjuvant rectal (NAR) score that incorporates weighted cT, ypT and ypN categories for disease-free survival (DFS) in 1191 patients with rectal carcinoma treated within the CAO/ARO/AIO-04 phase III trial.Patients and methodsCox regression models adjusted for treatment arm, resection status, and NAR score were used in multivariable analysis. The four Prentice criteria (PC1–4) were used to assess individual-level surrogacy of NAR for DFS.ResultsAfter a median follow-up of 50 months, the addition of oxaliplatin to fluorouracil-based chemoradiotherapy (CRT) significantly improved 3-year DFS [75.9% (95% confidence interval [CI] 72.30% to 79.50%) versus 71.3% (95% CI 67.60% to 74.90%); P = 0.034; PC 1) and resulted in a shift toward lower NAR groups (P = 0.034, PC 2) compared with fluorouracil-only CRT. The 3-year DFS was 91.7% (95% CI 88.2% to 95.2%), 81.8% (95% CI 78.4% to 85.1%), and 58.1% (95% CI 52.4% to 63.9%) for low, intermediate, and high NAR score, respectively (P < 0.001; PC 3). NAR score remained an independent prognostic factor for DFS [low versus high NAR: hazard ratio (HR) 4.670; 95% CI 3.106–7.020; P < 0.001; low versus intermediate NAR: HR 1.971; 95% CI 1.303–2.98; P = 0.001] in multivariable analysis. Notwithstanding the inherent methodological difficulty in interpretation of PC 4 to establish surrogacy, the treatment effect on DFS was captured by NAR, supporting satisfaction of individual-level PC 4.ConclusionOur study validates the prognostic role and individual-level surrogacy of NAR score for DFS within a large randomized phase III trial. NAR score could help oncologists to speed up response-adapted therapeutic decision, and further large phase III trial data sets should aim to confirm trial-level surrogacy.     

Impact of premenopausal status at breast cancer diagnosis in women entered on the placebo-controlled NCIC CTG MA17 trial of extended adjuvant letrozole

BackgroundMA17 showed improved outcomes in postmenopausal women given extended letrozole (LET) after completing 5 years of adjuvant tamoxifen.Patients and methodsExploratory subgroup analyses of disease-free survival (DFS), distant DFS (DDFS), overall survival (OS), toxic effects and quality of life (QOL) in MA17 were performed based on menopausal status at breast cancer diagnosis.ResultsAt diagnosis, 877 women were premenopausal and 4289 were postmenopausal. Extended LET was significantly better than placebo (PLAC) in DFS for premenopausal [hazard ratio (HR) = 0.26, 95% confidence interval (CI) 0.13–0.55; P = 0.0003] and postmenopausal women (HR = 0.67; 95% CI 0.51–0.89; P = 0.006), with greater DFS benefit in those premenopausal (interaction P = 0.03). In adjusted post-unblinding analysis, those who switched from PLAC to LET improved DDFS in premenopausal (HR = 0.15; 95% CI 0.03–0.79; P = 0.02) and postmenopausal women (HR = 0.45; 95% CI 0.22–0.94; P = 0.03).ConclusionsExtended LET after 5 years of tamoxifen was effective in pre- and postmenopausal women at diagnosis, and significantly better in those premenopausal. Women premenopausal at diagnosis should be considered for extended adjuvant therapy with LET if menopausal after completing tamoxifen.     

Prognosis Impact of the Lymph Node Ratio in Patients with Colon Adenocarcinoma: a Single-Centre Experience

Purpose

Recently, the positive lymph node ratio (LNR) is considered a new prognostic parameter on survival and time to progression for patients with colon cancer. The aim of this study was to determine the prognostic impact of the LNR as an independent factor for overall survival (OS) and disease-free survival (DFS) in patients with colon cancer regardless of their clinical stage.

Methods

We retrospectively identified 85 consecutive patients diagnosed with colon adenocarcinoma treated in our centre during 2010. We categorized patients according to a LNR cutoff of 0.25. Three-year OS and DFS were determined according to the Kaplan–Meier method. A Cox proportional model was used to assess the influence of other prognostic variables on each outcome.

Results

After median follow-up of 34.8 months, neither median OS nor DFS has been reached by any of the subgroups. Nevertheless, patients with a LNR?≥?0.25 exhibited a higher risk of death (hazard ratio, 3.10; 95 % confidence interval (CI), 1.38–7.01; log-rank test: p?=?0.006) and a shorter interval without progression (hazard ratio, 6.59; 95 % CI, 1.96–22.15; log-rank test: p?=?0.002.) than patients with LNR?<?0.25. After adjusting for prespecifed variables, the impact of a LNR?≥?0.25 was independently associated with OS (hazard ratio, 2.8; 95 % CI, 1.01–7.73; p?=?0.04) and DFS (hazard ratio, 7.07; 95 % CI, 1.23–40.45; p?=?0.03).

Conclusions

LNR was independently associated with OS and DFS in patients with colon adenocarcinoma regardless of its clinical stage.     

Neuroendocrine Carcinoma of the Urinary Bladder: A Large,Retrospective Study From the French Genito-Urinary Tumor Group

BackgroundNeuroendocrine carcinoma of the urinary bladder (NCUB) is rare, accounting for < 1% of bladder cancer cases, with scarce reported data available.Materials and MethodsWe retrospectively reviewed the data from patients with NCUB treated at French institutions. The objectives were to describe the patient characteristics, treatments received, and outcomes (ie, disease-free survival [DFS], progression-free survival, overall survival [OS]) and investigate the prognostic factors.ResultsFrom 1997 to 2017, we included 236 patients, 173 with early-stage NCUB and 63 with advanced-stage NCUB. For those with early-stage disease, the median DFS was better for the patients who had received cisplatin-based chemotherapy compared with carboplatin (hazard ratio [HR], 1.95; 95% confidence interval [CI], 1.1-3.46), with no difference found between the neoadjuvant and adjuvant settings (HR, 1.1; 95% CI, 0.61-1.97). The median OS was 36 months (95% CI, 29-43 months) for stage I and II, 26 months (95% CI, 18 months to not reached) for stage IIIA, 16 months (95% CI, 12-21 months) for stage IIIB. The HR for stage IIIB compared with stage I/II was 2.6 (95% CI, 1.5-4.4). The DFS at 6 months was associated with OS (HR, 7.8; 95% CI, 4.1-15.0). For patients with metastases at diagnosis who had received chemotherapy, the median progression-free survival was 9 months (95% CI, 8-11) for first-line cisplatin and 6 months (95% CI, 4-13 months) for carboplatin; the median OS was 13 months (95% CI, 9-15 months). A high-risk Bajorin score (HR, 11.5; 95% CI, 1.2-112.6) and the use of carboplatin (HR, 2.26; 95% CI, 1.03-4.96) were associated with worse outcomes.ConclusionsIn early-stage disease, a shorter DFS was associated with worse OS, and the use of cisplatin was associated with better OS. For the patients with metastases at diagnosis, a high-risk Bajorin score and the use of carboplatin were associated with worse outcomes.     

Overall survival benefit for sequential doxorubicin–docetaxel compared with concurrent doxorubicin and docetaxel in node-positive breast cancer—8-year results of the Breast International Group 02-98 phase III trial

BackgroundIn women with node-positive breast cancer, the Breast International Group (BIG) 02-98 tested the incorporation of docetaxel (Taxotere) into doxorubicin (Adriamycin)-based chemotherapy, and compared sequential and concurrent docetaxel. At 5 years, there was a trend for improved disease-free survival (DFS) with docetaxel. We present results at 8-year median follow-up and exploratory analyses within biologically defined subtypes.MethodsPatients were randomly assigned to one of four treatments: (i) sequential control: doxorubicin (A) (75 mg/m²) × 4 →classical cyclophosphamide, methotrexate, 5-fluorouracil (CMF); (ii) concurrent control: doxorubicin, cyclophosphamide (AC)(60/600 mg/m²) × 4 →CMF; (iii) sequential docetaxel: A (75 mg/m²) × 3 → docetaxel (T) (100 mg/m²) × 3 → CMF and (iv) concurrent docetaxel: AT(50/75 mg/m²) × 4 →CMF. The primary comparison evaluated docetaxel efficacy regardless of the schedule. Exploratory analyses were undertaken within biologically defined subtypes.ResultsTwo thousand eight hundred and eighty-seven patients were enrolled. After 93.4 months of median follow-up, there were 916 DFS events. For the primary comparison, there was no significant improvement in DFS from docetaxel [hazard ratio (HR) = 0.91, 95% confidence interval (CI) = 0.80–1.05, P = 0.187]. In secondary comparisons, sequential docetaxel significantly improved DFS compared with sequential control (HR = 0.81, 95% CI = 0.67–0.99, P = 0.036), and significantly improved DFS (HR = 0.84, 95% CI = 0.72–0.99, P = 0.035) and overall survival (OS) (HR = 0.79, 95% CI = 0.65–0.98, P = 0.028) compared with concurrent doxorubicin–docetaxel. Luminal-A disease had the best prognosis. HRs favored addition of sequential docetaxel in all subtypes, except luminal-A; but this observation was not statistically supported because of limited numbers.ConclusionWith further follow-up, the sequential docetaxel schedule resulted in significantly better OS than concurrent doxorubicin–docetaxel, and continued to show better DFS than sequential doxorubicin-based control.     

Resumption or persistence of menstruation after cytotoxic chemotherapy is a prognostic factor for poor disease-free survival in premenopausal patients with early breast cancer

BackgroundWe investigated the relationship between resumption or persistence of menstruation after cytotoxic chemotherapy (RM) and disease-free survival (DFS) in premenopausal patients with early breast cancer.MethodsMedical records from 872 patients who received cytotoxic chemotherapy for stage I to III breast cancer were retrospectively reviewed.ResultsThe median patient age was 41 years (range, 21–54) and the median follow-up duration was 6.2 years (range, 0.7–10.4). Six hundred ninety-two patients (79.4%) were hormone receptor (HR) positive and the majority of these received tamoxifen therapy after completing chemotherapy. The chemotherapy-induced amenorrhea (CIA) rate was 76.7% (n = 669), and 51.8% (n = 452) experienced RM during the follow-up period. One hundred twenty-one (13.9%) patients had persistent menstruation without CIA. DFS was significantly affected by younger age at diagnosis (≤35 years) (P = 0.013), tumor size > 2 cm (P < 0.001), node positivity (P < 0.001), HR negativity (P < 0.001), HER2 positivity (P = 0.010), and RM (P < 0.001). HR negativity [hazard ratio 1.7, 95% confidence interval (CI) 1.2–2.4, P = 0.006], tumor size > 2 cm (hazard ratio 2.1, 95% CI 1.4–3.0, P < 0.001), node positivity (hazard ratio 3.0, 95% CI 2.0–4.7, P < 0.001), and RM (hazard ratio 1.8, 95% CI 1.2–2.7, P = 0.004) remained significant factors for DFS on multivariate analysis.ConclusionsA considerable proportion of premenopausal patients treated with chemotherapy experienced RM after CIA. RM was a poor prognostic factor for DFS in premenopausal patients with early breast cancer.     

Role of major resection in pulmonary metastasectomy for colorectal cancer in the Spanish prospective multicenter study (GECMP-CCR)

BackgroundPatients with pulmonary metastases from colorectal cancer (CRC) may benefit from aggressive surgical therapy. The objective of this study was to determine the role of major anatomic resection for pulmonary metastasectomy to improve survival when compared with limited pulmonary resection.Patients and methodsData of 522 patients (64.2% men, mean age 64.5 years) who underwent pulmonary resections with curative intent for CRC metastases over a 2-year period were reviewed. All patients were followed for a minimum of 3 years. Disease-specific survival (DSS) and disease-free survival (DFS) were assessed with the Kaplan–Meier method. Factors associated with DSS and DFS were analyzed using a Cox proportional hazards regression model.ResultsA total of 394 (75.6%) patients underwent wedge resection, 19 (3.6%) anatomic segmentectomy, 5 (0.9%) lesser resections not described, 100 (19.3%) lobectomy, and 4 (0.8%) pneumonectomy. Accordingly, 104 (19.9%) patients were treated with major anatomic resection and 418 (80.1%) with lesser resection. Operations were carried out with video-assisted thoracoscopic surgery (VATS) in 93 patients. The overall DSS and DFS were 55 and 28.3 months, respectively. Significant differences in DSS and DFS in favor of major resection versus lesser resection (DSS median not reached versus 52.2 months, P = 0.03; DFS median not reached versus 23.9 months, P < 0.001) were found. In the multivariate analysis, major resection appeared to be a protective factor in DSS [hazard ratio (HR) 0.6, 95% confidence interval (CI) 0.41–0.96, P = 0.031] and DFS (HR 0.5, 95% CI 0.36–0.75, P < 0.001). The surgical approach (VATS versus open surgical resection) had no effect on outcome.ConclusionMajor anatomic resection with lymphadenectomy for pulmonary metastasectomy can be considered in selected CRC patient with sufficient functional reserve to improve the DSS and DFS. Further prospective randomized studies are needed to confirm the present results.     

Effect of Dose Ratio on Mitoxantrone and Daunorubicin in Acute Myeloid Leukemia: A Systematic Review and Meta-analysis of Randomized Controlled Trials

PurposeTo investigate the effects of mitoxantrone and daunorubicin in induced chemotherapy on complete remission (CR), death during induction therapy, overall survival (OS), disease-free survival (DFS), and relapse in patients of all ages with acute myeloid leukemia (AML).MethodsWe searched published reports at the Medline, Embase, and Cochrane Databases as well as other databases from inception through July 2019. There was no restriction on date of publication or language (PROSPERO registration CRD42018095843).ResultsWe enrolled 12 randomized controlled trials that included data of 4583 AML patients whose disease was untreated or relapsed/refractory, and compared the CR, death during induction therapy, DFS, and OS between mitoxantrone and daunorubicin. Mitoxantrone significantly increased the CR rate (relative risk = 1.07; 95% confidence interval [CI], 1.01, 1.14; P = .03) and DFS (hazard ratio = 0.87; 95% CI, 0.79, 0.96; P = .005) compared to daunorubicin. However, there was no significant difference in death during induction therapy (relative risk = 1.00; 95% CI, 0.81, 1.24; P = .99) and OS (hazard ratio = 0.94; 95% CI, 0.87, 1.01; P = .077) between the two drugs.ConclusionAlthough more studies are needed to compare mitoxantrone with higher-dose daunorubicin, the results showed that compared to daunorubicin, mitoxantrone can significantly improve CR and DFS in patients of all ages. These findings suggest that mitoxantrone may be a better choice than daunorubicin as an induction chemotherapy agent for AML patients, especially in developing countries.     

Zoledronic acid combined with adjuvant endocrine therapy of tamoxifen versus anastrozol plus ovarian function suppression in premenopausal early breast cancer: final analysis of the Austrian Breast and Colorectal Cancer Study Group Trial 12

These final results from ABCSG-12 confirm that twice-yearly ZOL safely enhances the efficacy of adjuvant endocrine therapy. Tamoxifen together with Goserelin for now remains the endocrine standard of care. In general, overall survival of more than 95% at 8 years' median follow-up supports the efficacy of endocrine-only regimens in this premenopausal patient population.BackgroundZoledronic acid (ZOL) plus adjuvant endocrine therapy significantly improved disease-free survival (DFS) at 48- and 62-month follow-up in the ABCSG-12 trial. We present efficacy results of a final additional analysis after 94.4 months.Patients and methodsPatients were premenopausal women who had undergone primary surgery for stage I/II estrogen-receptor-positive and/or progesterone-receptor-positive breast cancer with <10 positive lymph nodes, and were scheduled for standard goserelin therapy. All 1803 patients received goserelin (3.6 mg every 28 days) and were randomized to tamoxifen (20 mg/days) or anastrozole (1 mg/days), both with or without ZOL (4 mg every 6 months) for 3 years. The primary end point was DFS; recurrence-free survival and overall survival (OS) were secondary end points.ResultsAfter 94.4-month median follow-up (range, 0–114 months), relative risks of disease progression [hazard ratio (HR) = 0.77; 95% confidence interval (CI) 0.60–0.99; P = 0.042] and of death (HR = 0.66; 95% CI 0.43–1.02; P = 0.064) are still reduced by ZOL although no longer significant at the predefined significance level. Overall, 251 DFS events and 86 deaths were reported. Absolute risk reductions with ZOL were 3.4% for DFS and 2.2% for OS. There was no DFS difference between tamoxifen alone versus anastrozole alone, but there was a pronounced higher risk of death for anastrozole-treated patients (HR = 1.63; 95% CI 1.05–1.45; P = 0.030). Treatments were generally well tolerated, with no reports of renal failure or osteonecrosis of the jaw.ConclusionThese final results from ABCSG 12 suggest that twice-yearly ZOL enhances the efficacy of adjuvant endocrine treatment, and this benefit is maintained long-term.ClinicalTrials.govNCT00295646 (http://www.clinicaltrials.gov/ct2/results?term=00295646).     

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

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

Esophagectomy With Three-Field Versus Two-Field Lymphadenectomy for Middle and Lower Thoracic Esophageal Cancer: Long-Term Outcomes of a Randomized Clinical Trial

IntroductionThe optimal extent of lymphadenectomy during esophagectomy remains unclear. In this trial, we aim to clarify whether three-field (cervical-thoracic-abdominal) lymphadenectomy improved patient survival over two-field (thoracic-abdominal) lymphadenectomy for esophageal cancer.MethodsBetween March 2013 and November 2016, a total of 400 patients with middle and lower thoracic esophageal cancer were included and randomly assigned to undergo esophagectomy with either three- or two-field lymphadenectomy at a 1:1 ratio. Analyses were done according to the intention-to-treat principle. The primary end point was overall survival (OS), calculated from the date of randomization to the date of death from any cause.ResultsDemographic characteristics were similar in the two arms. The median follow-up time was 55 months (95% confidence interval [CI]: 52–58). OS (hazard ratio [HR] = 1.019, 95% CI: 0.727–1.428, p = 0.912) and the disease-free survival (DFS) (HR = 0.868, 95% CI: 0.636–1.184, p = 0.371) were comparable between the two arms. The cumulative 5-year OS was 63% in the three-field arm, as compared with 63% in the two-field arm; 5-year DFS was 59% and 53%, respectively. On the basis of whether the patients had mediastinal or abdominal lymph node metastasis or not, OS was also comparable between the two arms. In this cohort, only advanced tumor stage (pathologic TNM stages III–IV) was identified as the risk factor associated with reduced OS (HR = 3.330, 95% CI: 2.140–5.183, p < 0.001).ConclusionsFor patients with middle and lower thoracic esophageal cancer, there was no improvement in OS or DFS after esophagectomy with three-field lymphadenectomy over two-field lymphadenectomy.     

Disease-Free Survival and Time to Complete Response After Definitive Chemoradiotherapy for Squamous-Cell Carcinoma of the Anus According to HIV Infection

BackgroundThe standard treatment for localized squamous-cell carcinoma of the anal canal is definitive chemoradiotherapy. A meta-analysis of published studies conducted by our group showed significantly lower rates of disease-free survival (DFS) and overall survival at 3 years among HIV-positive patients. We aimed to compare detailed treatment outcomes between the groups of HIV-positive and -negative patients.Patients and MethodsWe performed a retrospective multicenter study of a comparative cohort of consecutive patients with histologic diagnosis of localized squamous-cell carcinoma of the anal canal who received definitive chemoradiotherapy. Patients’ characteristics and outcomes were compared according to HIV status. The primary end points were time to complete response (CR) and DFS time.ResultsFrom June 2001 to September 2018, a total of 185 patients were included; 43 (30.2%) were HIV positive and 142 (69.8%) were HIV negative. The overall CR rates were 67.4% and 91.5% for HIV-positive and -negative patients, respectively (P < .001). The median follow-up was 47.8 months and the median time to experience CR was 7.8 months (95% confidence interval [CI], 5.7-10.5) for HIV-positive versus 4.89 months (95% CI, 4.54-5.25) for HIV-negative (P < .001) patients. The median DFS times were 79.7 months (95% CI, 56.8-102.6) and 127.9 months (95% CI, 112.6-143.2) for HIV-positive and -negative patients, respectively (P = .02). There was a trend toward greater grade 3/4 toxicity in the HIV-positive group.ConclusionHIV-positive patients take longer to experience CR and present worse DFS. These findings have clinical implications because waiting longer to define CR among these patients may prevent unnecessary anorectal amputations.     

Clinical Outcomes of Patients With Breast Cancer in a Phase I Clinic: The M. D. Anderson Cancer Center Experience

PurposePatients with metastatic breast cancer (MBC) refractory to standard therapy have a poor prognosis. We assessed prognostic factors and clinical outcomes for patients with MBC referred to a phase I clinic focused primarily on targeted agents.Patients and MethodsWe reviewed the medical records of sequential patients with MBC who presented to our phase I clinic between September 2004 and May 2008 to assess baseline patient characteristics, overall survival (OS), and clinical benefit.ResultsA total of 92 patients were identified, with a median age of 53 years (range, 28–83 years). The median number of previous therapies was 5 (range, 1–16 therapies). Of 92 patients, 78 were eligible for and offered ≥ 1 phase I clinical trial. With a median follow-up of 7.4 months, the median OS was 6.7 months (95% CI, 5.2–9.7). In multivariate analysis, independent factors predicting shorter survival were ≥ 10 previous treatments (vs. < 10 previous treatments; hazard ratio [HR], 3.27; 95% CI, 1.37–7.81; P = .008), Eastern Cooperative Oncology Group (ECOG) performance status (PS) 2/3 (vs. 0/1; HR, 2.92; 95% CI, 1.28–6.66; P = .01), and albumin level < 3.5 g/dL (vs. > 3.5 g/dL; HR, 2.88; 95% CI, 1.41–5.89; P = .004).ConclusionPatients with locally advanced or metastatic breast cancer referred for our phase I studies had a median survival of 6.7 months. Heavily pretreated disease, poor ECOG PS, and/or low albumin levels were associated with significantly shorter survival in a multivariate analysis.     

The good,the bad and the ugly: a tale of miR-101, miR-21 and miR-155 in pancreatic intraductal papillary mucinous neoplasms

BackgroundThis multicenter study evaluated three candidate microRNAs (miRNAs) (miR-21, miR-155 and miR-101) as potential biomarkers in intraductal papillary mucinous neoplasms (IPMNs) of the pancreas.Patients and methodsmiRNA expression was quantified by quantitative RT-PCR in 86 laser-microdissected specimens, including 65 invasive IPMNs, 16 non-invasive IPMNs and 5 normal pancreatic ductal tissues. Univariate and multivariate analyses compared miRNAs and clinical parameters with overall (OS) and disease-free survival (DFS).ResultsmiR-21 and miR-155 were up-regulated in invasive IPMNs compared with non-invasive IPMNs, as well as in non-invasive IPMNs compared with normal tissues. Conversely, miR-101 levels were significantly higher in non-invasive IPMNs and normal tissues compared with invasive IPMNs. High levels of miR-21 were associated with worse OS [hazard ratio (HR) = 2.47, 95% confidence interval (CI) = 1.37–5.65, P = 0.0047]. Patients with high-miR-21 expression also had a shorter median DFS (10.9 versus 29.9 months, P = 0.01). Multivariate analysis confirmed miR-21 as independently prognostic for mortality and disease progression (death risk: HR = 3.3, 95% CI = 1.5–7.0, P = 0.02; progression risk: HR = 2.3, 95% CI = 1.2–4.8, P = 0.02), as well as positive lymph-node status (death risk: HR = 2.6, 95% CI = 1.1–6.3, P = 0.03; progression risk: HR = 2.2, 95% CI = 1.0–4.8, P = 0.04).ConclusionsmiR-21, miR-155 and miR-101 showed significant differences in invasive versus non-invasive IPMNs. miR-21 emerged as an independent prognostic biomarker in invasive IPMNs and should be validated in prospective studies.     

Chronicle: results of a randomised phase III trial in locally advanced rectal cancer after neoadjuvant chemoradiation randomising postoperative adjuvant capecitabine plus oxaliplatin (XELOX) versus control

BackgroundIn stage III colon cancer, oxaliplatin/5-fluorouracil (5-FU)-based adjuvant chemotherapy (FOLFOX) improves disease-free survival (DFS) and overall survival (OS). In rectal adenocarcinoma following neoadjuvant chemoradiation (CRT), we examined the benefit of postoperative adjuvant capecitabine and oxaliplatin (XELOX) chemotherapy.MethodsEligible patients were randomly assigned following fluoropyrimidine-based CRT and curative resection to observation or six cycles of XELOX. The primary end point was DFS; secondary end points were acute toxicity and OS. 390 patients were required in each arm, to detect an improvement in 3-year DFS from 40% to 50.5%, with 85% power and two-sided 5% significance level.ResultsThe study closed prematurely in 2008 because of poor accrual. Only 113 patients were randomly assigned to either observation (n = 59) or XELOX (n = 54). Compliance was poor, 93% allocated chemotherapy started and 48% completed six cycles. Protocolised dose reductions in XELOX were 39%, and levels of G3/G4 toxicity 40%. After a median follow-up of 44.8 months, 16 patients (27%) in the observation arm had relapsed or died compared with 12 patients (22%) in XELOX. The 3-year DFS rate was 78% with XELOX and 71% with observation [hazard ratio (HR) for DFS = 0.80; 95% confidence interval (CI) 0.38–1.69; P = 0.56]. The 3-year OS for XELOX and observation were 89% and 88%, respectively (HR for OS = 1.18; 95% CI 0.43–3.26; P = 0.75).ConclusionsThe observed improvement in DFS for adjuvant XELOX and similar OS were not statistically significant, as expected given the small number of patients and consequent low power. Our findings support the need for trials that test the role of neoadjuvant chemotherapy.ClinicalTrials.gov IdentifierNCT00427713.     

Capecitabine versus 5-fluorouracil/folinic acid as adjuvant therapy for stage III colon cancer: final results from the X-ACT trial with analysis by age and preliminary evidence of a pharmacodynamic marker of efficacy

BackgroundThis multicenter randomized trial compared oral capecitabine with bolus i.v. 5-fluorouracil (5-FU)/folinic acid (FA) as adjuvant therapy for stage III colon cancer.Patients and methodsPatients were assigned to 24 weeks of capecitabine 1250 mg/m² twice daily on days 1–14 every 3 weeks or 5-FU/FA (Mayo Clinic regimen). The primary end point was disease-free survival (DFS).ResultsThe intent-to-treat population received capecitabine (n = 1004) or 5-FU/FA (n = 983). With a median follow-up of 6.9 years, capecitabine was at least equivalent to 5-FU/FA in terms of DFS [hazard ratio (HR) = 0.88; 95% confidence interval (CI) 0.77–1.01] and overall survival (OS) (HR = 0.86; 95% CI 0.74–1.01); the 95% CI upper limits were significantly less than the predefined noninferiority margins of 1.20 (P < 0.0001) and 1.14 (P < 0.001), respectively. This pattern was maintained in all subgroups, including patients aged ≥70 years. Preplanned multivariate analyses showed that capecitabine had statistically significant beneficial effects on DFS (P = 0.021) and OS (P = 0.020) versus 5-FU/FA. A post hoc analysis suggested that the occurrence of hand–foot syndrome may be associated with better outcomes in capecitabine recipients.ConclusionOral capecitabine is an effective alternative to bolus 5-FU/FA as adjuvant treatment of patients with stage III colon cancer with efficacy benefits maintained at 5 years and in older patients.