Correction: Quality of life under extended continuous versus intermittent adjuvant letrozole in lymph node-positive, early breast cancer patients: the SOLE randomised phase 3 trial.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Treatment-induced symptoms, depression and age as predictors of sexual problems in premenopausal women with early breast cancer receiving adjuvant endocrine therapy.

PURPOSE: Sexual dysfunction is an important concern of premenopausal women with early breast cancer. We investigated predictors of sexual problems in two randomized controlled trials. METHODS: A subset of patients enrolled in TEXT and SOFT completed global and symptom-specific quality-of-life indicators, CES-Depression and MOS-Sexual Problems measures at baseline, six, 12 and 24 months. Mixed models tested the association of changes in treatment-induced symptoms (baseline to 6 months), depression at 6 months, and age at randomization with changes in sexual problems over 2 years. RESULTS: Sexual problems increased by 6 months and persisted at this level. Overall, patients with more severe worsening of vaginal dryness, sleep disturbances and bone or joint pain at 6 months reported a greater increase in sexual problems at all time-points. Depression scores were significantly associated with sexual problems in the short-term. All other symptoms had a smaller impact on sexual problems. Age was not associated with sexual problems at any time-point. CONCLUSION: Among several key symptoms, vaginal dryness, sleep disturbance, and bone and joint pain significantly predicted sexual problems during the first 2 years. Early identification of these symptoms may contribute to timely and tailored interventions.

Quality of life under extended continuous versus intermittent adjuvant letrozole in lymph node-positive, early breast cancer patients: the SOLE randomised phase 3 trial.

BACKGROUND: In the phase III SOLE trial, the extended use of intermittent versus continuous letrozole for 5 years did not improve disease-free survival in postmenopausal women with hormone receptor-positive breast cancer. Intermittent therapy with 3-month breaks may be beneficial for patients' quality of life (QoL). METHODS: In the SOLE QoL sub-study, 956 patients completed the Breast Cancer Prevention Trial (BCPT) symptom and further QoL scales up to 24 months after randomisation. Differences in change of QoL from baseline between the two administration schedules were tested at 12 and 24 months using repeated measures mixed-models. The primary outcome was change in hot flushes at 12 months. RESULTS: There was no difference in hot flushes at 12 months between the two schedules, but patients receiving intermittent letrozole reported significantly more improvement at 24 months. They also indicated less worsening in vaginal problems, musculoskeletal pain, sleep disturbance, physical well-being and mood at 12 months. Overall, 25-30% of patients reported a clinically relevant worsening in key symptoms and global QoL. CONCLUSION: Less symptom worsening was observed during the first year of extended treatment with the intermittent administration. For women experiencing an increased symptom burden of extended adjuvant endocrine therapy, an intermittent administration is a safe alternative. CLINICAL TRIAL INFORMATION: Clinical trial information: NCT00651456.

Adjuvant ovarian function suppression and cognitive function in women with breast cancer.

BACKGROUND: To examine the effect on cognitive function of adjuvant ovarian function suppression (OFS) for breast cancer. METHODS: The Suppression of Ovarian Function (SOFT) trial randomised premenopausal women with hormone receptor-positive breast cancer to 5 years adjuvant endocrine therapy with tamoxifen+OFS, exemestane+OFS or tamoxifen alone. The Co-SOFT substudy assessed objective cognitive function and patient reported outcomes at randomisation (T0), and 1 year later (T1); the primary endpoint was change in global cognitive function, measured by the composite objective cognitive function score. Data were compared for the pooled tamoxifen+OFS and exemestane+OFS groups vs the tamoxifen alone group using the Wilcoxon rank-sum test. RESULTS: Of 86 participants, 74 underwent both T0 and T1 cognitive testing; 54 randomised to OFS+ either tamoxifen (28) or exemestane (26) and 20 randomised to tamoxifen alone. There was no significant difference in the changes in the composite cognitive function scores between the OFS+ tamoxifen or exemestane groups and the tamoxifen group (mean±s.d., -0.21±0.92 vs -0.04±0.49, respectively, P=0.71, effect size=-0.20), regardless of prior chemotherapy status, and adjusting for baseline characteristics. CONCLUSIONS: The Co-SOFT study, although limited by small samples size, provides no evidence that adding OFS to adjuvant oral endocrine therapy substantially affects global cognitive function.

A phase III randomized trial of high-dose CEOP + filgrastim versus standard-dose CEOP in patients with non-Hodgkin lymphoma: 10-year follow-up data: Australasian Leukaemia and Lymphoma Group (ALLG) NHL07 trial.

Increasing dose intensity (DI) of chemotherapy for patients with aggressive non-Hodgkin lymphoma (NHL) may improve outcomes at the cost of increased toxicity. This issue was addressed in a randomized trial aiming to double the DI of myelosuppressive drugs. Between 1994 and 1999, 250 patients with previously untreated aggressive NHL were randomized to treatment with six cycles of 3-weekly standard (s) or intensive (i) chemotherapy: s-CEOP-cyclophosphamide 750, epirubicin 75, vincristine 1.4 mg/m(2) all on day 1, and prednisolone 100 mg days 1-5; i-CEOP-cyclophosphamide 1,500, epirubicin 150, vincristine 1.4 mg/m(2) all on day 1, and prednisolone 100 mg days 1-5. Primary endpoint was 5-year overall survival (OS). Relative to s-CEOP patients, i-CEOP patients achieved a 78% increase in the DI of cyclophosphamide and epirubicin. Despite this, there was no significant difference in any outcome: 5-year OS (56.7% i-CEOP; 55.1% s-CEOP; P = 0.80), 5-year progression free survival (PFS; 41% i-CEOP; 43% s-CEOP; P = 0.73), 5-year time to progression (TTP; 44% i-CEOP; 47% s-CEOP; P = 0.72), or complete remission (CR) + unconfirmed CR (CRu) rates (53% i-CEOP; 59% s-CEOP; P = 0.64). Long-term follow up at 10 years also showed no significant differences in OS, PFS, or TTP. The i-CEOP arm had higher rates of febrile neutropenia (70 vs. 26%), hospitalisations, blood product utilisation, haematological and gastrointestinal toxicities, and lower quality of life scores during treatment, although without significant differences 6-month later. In the treatment of aggressive NHL in the prerituximab era, increasing DI did not result in improved outcomes, while at the same time lead to increased toxicity.

Phase III, randomized, double-blind, placebo-controlled study of modafinil for fatigue in patients treated with docetaxel-based chemotherapy.

PURPOSE: Modafinil has been reported to benefit a subgroup of patients suffering severe fatigue while undergoing chemotherapy. Docetaxel is associated with fatigue that may lead to premature therapy withdrawal. We investigated whether modafinil could reduce fatigue during docetaxel chemotherapy. METHODS: This multicenter, randomized, double-blind, placebo-controlled study evaluated the efficacy of modafinil in patients with metastatic prostate or breast cancer undergoing docetaxel chemotherapy (every 21 days; minimum dose 50 mg/m(2)). At the start of their third or subsequent chemotherapy cycle, patients with significant docetaxel-associated fatigue were randomized to receive concurrent modafinil 200 mg/day or placebo for 15 days ("treatment periods" (TP)). Docetaxel was continued for up to four further cycles. Fatigue was evaluated with the fatigue component of the MD Anderson Symptom Inventory (MDASI). The primary endpoint was cumulative MDASI area under the curve (AUC) during the first 7 days of study medication during TP1 and TP2. RESULTS: Evaluable data were available from 83 patients (65 with prostate cancer). There was no statistically significant difference between the two treatment arms for the primary endpoint (MSADI AUC3-10 35.9 vs 39.6; 95 % confidence interval -8.9, 1.4; P=0.15). Overall toxicity was comparable between treatment groups; however, the incidence of grade ≤ 2 nausea and vomiting was higher in the modafinil arm (45.4 vs 25 %). CONCLUSIONS: Assessing and managing chemotherapy-related fatigue remains a major challenge. There was a lack of difference between the two arms in the planned primary endpoint. However, there was a modest but consistent trend towards improvement of docetaxel-related fatigue in those treated with modafinil. Based on the study findings, modafinil for the treatment of fatigue associated with docetaxel chemotherapy elicits modest improvements. Larger, longer term, randomized, controlled studies are required to clarify the exact role of modafinil in the treatment of docetaxel-related fatigue.

Metastatic urothelial carcinoma of the bladder with sarcomatoid differentiation showing large cell neuroendocrine transformation in the liver; an unusual behaviour of a rare disease.

Metastatic urothelial carcinoma of the bladder is generally considered to be an aggressive disease with many recognised variants, however what is unique about our patient is the metastatic transformation from a urothelial primary malignancy with sarcomatoid variation to a neuroendocrine deposit within the liver. From what we have identified, this pattern of pathological transformation has not been reported for a urothelial malignancy in the literature. We present a 64 year old male who we believe is the first reported case of a primary urothelial malignancy presenting de-novo with metastatic liver deposits showing neuro-endocrine transformation.

Decline in Left Ventricular Ejection Fraction Following Anthracyclines Predicts Trastuzumab Cardiotoxicity.

OBJECTIVES: The aim of CATS (Cardiotoxicity of Adjuvant Trastuzumab Study) was to prospectively assess clinical, biochemical, and genomic predictors of trastuzumab-related cardiotoxicity (TRC). BACKGROUND: Cardiac dysfunction is a common adverse effect of trastuzumab. Studies to identify predictive biomarkers for TRC have enrolled heterogeneous populations and yielded mixed results. METHODS: A total of 222 patients with early-stage human epidermal growth factor receptor 2-positive breast cancer scheduled to receive adjuvant anthracyclines followed by 12 months of trastuzumab were prospectively recruited from 17 centers. Left ventricular ejection fraction (LVEF), troponin T, and N-terminal prohormone of brain natriuretic peptide were measured at baseline, post-anthracycline, and every 3 months during trastuzumab. Germline single-nucleotide polymorphisms in ERBB2, FCGR2A, and FCGR3A were analyzed. TRC was defined as symptomatic heart failure; cardiac death, arrhythmia, or infarction; a decrease in LVEF of >15% from baseline; or a decrease in LVEF of >10% to <50%. RESULTS: TRC occurred in 18 of 217 subjects (8.3%). Lower pre-anthracycline LVEF and greater interval decline in LVEF from pre- to post-anthracycline were each associated with TRC on multivariate analyses (odds ratio: 3.9 [p = 0.0001] and 7.9 [p < 0.0001] for a 5% absolute change in LVEF). Higher post-anthracycline N-terminal prohormone of brain natriuretic peptide level was associated with TRC on univariate but not multivariate analyses. There were no associations between troponin T or ERBB2/FGCR polymorphisms and TRC. Baseline LVEF and LVEF change post-anthracycline were used to generate a "low-risk TRC score" to identify patients with low TRC incidence. CONCLUSIONS: Low baseline LVEF and greater LVEF decline post-anthracycline were both independent predictors of TRC. The other biomarkers did not further improve the ability to predict TRC. (Cardiotoxicity of Adjuvant Trastuzumab [CATS]; NCT00858039).

Low-Dose Oral Cyclophosphamide and Methotrexate Maintenance for Hormone Receptor-Negative Early Breast Cancer: International Breast Cancer Study Group Trial 22-00.

PURPOSE: To evaluate the benefit of low-dose cyclophosphamide and methotrexate (CM) maintenance, which previously demonstrated antitumor activity and few adverse effects in advanced breast cancer, in early breast cancer. PATIENTS AND METHODS: International Breast Cancer Study Group (IBCSG) Trial 22-00, a randomized phase III clinical trial, enrolled 1,086 women (1,081 intent-to-treat) from November 2000 to December 2012. Women with estrogen receptor- and progesterone receptor-negative (< 10% positive cells by immunohistochemistry) early breast cancer any nodal and human epidermal growth factor receptor 2 status, were randomly assigned anytime between primary surgery and 56 days after the first day of last course of adjuvant chemotherapy to CM maintenance (cyclophosphamide 50 mg/day orally continuously and methotrexate 2.5 mg twice/day orally on days 1 and 2 of every week for 1 year) or to no CM. The primary end point was disease-free survival (DFS), which included invasive recurrences, second (breast and nonbreast) malignancies, and deaths. RESULTS: After a median of 6.9 years of follow-up, DFS was not significantly better for patients assigned to CM maintenance compared with patients assigned to no CM, both overall (hazard ratio [HR], 0.84; 95% CI, 0.66 to 1.06;P = .14) and in triple-negative (TN) disease (n = 814; HR, 0.80; 95% CI, 0.60 to 1.06). Patients with TN, node-positive disease had a nonstatistically significant reduced HR (n = 340; HR, 0.72; 95% CI, 0.49 to 1.05). Seventy-one (13%) of 542 patients assigned to CM maintenance did not start CM. Of 473 patients who received at least one CM maintenance dose (including two patients assigned to no CM), 64 (14%) experienced a grade 3 or 4 treatment-related adverse event; elevated serum transaminases was the most frequently reported (7%), followed by leukopenia (2%). CONCLUSION: CM maintenance did not produce a significant reduction in DFS events in hormone receptor-negative early breast cancer. The trend toward benefit observed in the TN, node-positive subgroup supports additional exploration of this strategy in the TN, higher-risk population.

Multicenter randomized, open-label phase II trial of sequential erlotinib and gemcitabine compared with gemcitabine monotherapy as first-line therapy in elderly or ECOG PS two patients with advanced NSCLC.

AIM: The potential beneficial interaction between erlotinib and chemotherapy may require sequencing or pharmacodynamic separation. The aim of this study was to evaluate the efficacy and tolerance of sequential erlotinib and gemcitabine versus gemcitabine monotherapy as first-line therapy in elderly or ECOG PS-2 patients with advanced non-small cell lung carcinoma. METHODS: The primary objective of this multicenter randomized Phase II study was progression-free survival (PFS). Secondary objectives were overall response rate (ORR), disease control rate, response duration, overall survival and safety. Patients were randomized to either gemcitabine (1250 mg/m2 Day 1, 8 q28 days) followed by erlotinib (150 mg/day on day 15 through day 28), (EG-arm), or gemcitabine monotherapy (1000 mg/m2 Days 1, 8, 15 q28 days), (G-arm) for up to six cycles. RESULTS: Fifty-four patients were recruited, 28 G-arm and 26 EG-arm. Overall, efficacy results were not significantly different between study arms. Median PFS and ORR for the G- versus EG-arms were 8.0 versus 10.3 weeks (hazard ratio 1.3; 95% confidence interval [0.63;2.68]; P=0.48) and 7.1 versus 3.8 percent respectively (difference -3.30; 95% confidence interval [-17.5;10.9]). The majority of adverse events (AEs) in both arms were Grade 1-2. The commonest AEs recorded in the EG- and G-arms were rash-like events (65 percent) and nausea (42 percent) respectively. Four patients (17 percent) in EG-arm and five (16 percent) in G-arm experienced at least one treatment-related serious AE. CONCLUSIONS: In this study, patients with non-small cell lung carcinoma at ECOG PS-2 or aged ≥70 years derived no efficacy advantage from sequential erlotinib in combination with gemcitabine relative to gemcitabine alone. No unexpected safety findings were noted.

Prevention of aromatase inhibitor-induced bone loss with alendronate in postmenopausal women: The BATMAN Trial.

UNLABELLED: Postmenopausal women on aromatase inhibitors (AI) are at risk of aromatase inhibitor-associated bone loss (AIBL) and fractures. In 2005 Osteoporosis Australia proposed an algorithm for bisphosphonate intervention. Three hundred and three postmenopausal women with early breast cancer (EBC) were enrolled (osteoporotic, n=25; osteopaenic, n=146; normal bone mineral density (BMD), n=126). Weekly alendronate (70 mg) treatment efficacy as triggered by the algorithm in preventing bone loss was evaluated. All patients received anastrozole (1 mg daily), calcium and vitamin D. RESULTS: All osteoporotic patients received alendronate at baseline. Eleven out of the 146 (7.5%) osteopaenic patients commenced alendronate within 18 months of participation and eleven commenced after. One hundred and twenty four out of the 146 (84.9%) osteopaenic patients and all 126 with normal baseline BMD did not trigger the algorithm. At three years, lumbar spine mean BMD increased (15.6%, p<0.01) in the osteoporotic group. BMD in the osteopaenic group with early intervention significantly increased at three years (6.3%, p=0.02). No significant change was seen in the late intervention group. No change was observed in those with osteopaenia without alendronate. There was a significant drop in lumbar spine (-5.4%) and hip (-4.5%) mean BMD, in the normal BMD group, none of whom received alendronate. Fracture data will be presented. CONCLUSION: In postmenopausal women with endocrine-responsive EBC, BMD improved over time when a bisphosphonate is administered with anastrozole in osteoporotic patients using an osteoporosis schedule. Subjects with normal baseline BMD experienced the greatest BMD loss, although none became osteoporotic.

The median informs the message: accuracy of individualized scenarios for survival time based on oncologists' estimates.

PURPOSE: To determine the accuracy and usefulness of oncologists' estimates of survival time in individual patients with advanced cancer. PATIENTS AND METHODS: Twenty-one oncologists estimated the "median survival of a group of identical patients" for each of 114 patients with advanced cancer. Accuracy was defined by the proportions of patients with an observed survival time bounded by prespecified multiples of their estimated survival time. We expected 50% to live longer (or shorter) than their oncologist's estimate (calibration), 50% to live from half to double their estimate (typical scenario), 5% to 10% to live ≤ one quarter of their estimate (worst-case scenario), and 5% to 10% to live three or more times their estimate (best-case scenario). Estimates within 0.67 to 1.33 times observed survival were deemed precise. Discriminative value was assessed with Harrell's C-statistic and prognostic significance with proportional hazards regression. RESULTS: Median survival time was 11 months. Oncologists' estimates were relatively well-calibrated (61% shorter than observed), imprecise (29% from 0.67 to 1.33 times observed), and moderately discriminative (Harrell C-statistic 0.63; P = .001). The proportion of patients with an observed survival half to double their oncologist's estimate was 63%, ≤ one quarter of their oncologist's estimate was 6%, and three or more times their oncologist's estimate was 14%. Independent predictors of observed survival were oncologist's estimate (hazard ratio [HR] = 0.92; P = .004), dry mouth (HR = 5.1; P < .0001), alkaline phosphatase more than 101 U/L (HR = 2.8; P = .0002), Karnofsky performance status ≤ 70 (HR = 2.3; P = .007), prostate primary (HR = 0.23; P = .002), and steroid use (HR = 2.4; P = .02). CONCLUSION: Oncologists' estimates of survival time were relatively well-calibrated, moderately discriminative, independently associated with observed survival, and a reasonable basis for estimating worst-case, typical, and best-case scenarios for survival.

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.

Effect of sertraline on symptoms and survival in patients with advanced cancer, but without major depression: a placebo-controlled double-blind randomised trial.

BACKGROUND: Depression, anxiety, fatigue, and impaired wellbeing are common, important, and closely related in advanced cancer. We aimed to identify the effects of an established antidepressant on these symptoms and survival in patients with advanced cancer who did not have major depression as assessed by clinicians. METHODS: Between July, 2001, and February, 2006, 189 patients with advanced cancer were randomly assigned sertraline 50 mg (n=95), or placebo (n=94), once per day. The primary outcome was depression as assessed by the Centre for Epidemiologic Studies Depression scale (CES-D); the main secondary outcomes were: anxiety as assessed by Hospital Anxiety and Depression Scales (HADS-A); overall quality of life and fatigue as assessed by Functional Assessment of Cancer Therapy General and Fatigue scales (FACT-G and FACT-F, respectively); and clinicians' ratings of quality of life by use of Spizter's Quality of Life Index (SQLI). Multiple measures were used for corroboration of the most important outcomes. Primary analyses were done by intention to treat and were based on scale scores at 4 weeks and 8 weeks. The benefits of sertraline compared with placebo are expressed on a range from +100 (ie, maximum benefit) to -100 (ie, maximum harm); a difference of 10 was deemed clinically significant. This clinical trial is registered at Current Controlled Trials website http://www.controlled-trials.com/ISRCTN72466475. FINDINGS: Sertraline had no significant effect (scale, benefit over placebo [95% CI]) on depression (CES-D 0.4 [-2.6 to 3.4]), anxiety (HADS-A 2.0 [-1.5 to 5.5]), fatigue (FACT-F 0.3 [-4.3 to 4.9]), overall quality of life (FACT-G 1.7 [-1.3 to 4.7]), or clinicians' ratings (SQLI 2.0 [-2.5 to 6.5]), and the 95% CI ruled out a clinically significant benefit for all main outcomes. Sertraline was discontinued more often and earlier than was placebo (hazard ratio 1.46 [1.03-2.06], p=0.03). Recruitment was stopped after the first planned interim analysis in February 2006 (n=150) showed that survival was longer in patients assigned placebo than in patients assigned sertraline (unadjusted hazard ratio 1.60 [95% CI 1.04-2.45], log-rank p=0.04; adjusted hazard ratio 1.62 [1.06-2.41], Cox model p=0.02). However, at the final analysis in July 2006 of all patients (n=189) and with longer follow-up, survival did not differ significantly between the treatment groups (unadjusted hazard ratio 1.35 [0.95-1.91], log-rank p=0.09; adjusted hazard ratio 1.27 [0.87-1.84], Cox model p=0.20). The trial was closed because it had ruled out a significant benefit of sertraline. INTERPRETATION: Sertraline did not improve symptoms, wellbeing, or survival in patients with advanced cancer who do not have major depression, and should be reserved for those with a proven indication.

Palifermin reduces the incidence of oral mucositis in patients with metastatic colorectal cancer treated with fluorouracil-based chemotherapy.

PURPOSE: To characterize the efficacy and safety of palifermin in reducing the incidence of oral mucositis (OM) and diarrhea when administered to patients with metastatic colorectal cancer (CRC) receiving fluorouracil/leucovorin (FU/LV) chemotherapy. PATIENTS AND METHODS: Patients (N = 64) were randomly assigned to receive either placebo or palifermin (40 microg/kg for 3 consecutive days) before each of two consecutive cycles of chemotherapy with FU/LV. The incidence of OM and diarrhea, safety, disease progression, and survival were evaluated. RESULTS: Thirty-six patients received placebo and 28 patients received palifermin. The incidence of WHO grade 2 or higher OM was lower in patients who received palifermin compared with placebo (29% v 61% in cycle 1; 11% v 47% in cycle 2). FU dose reductions in the second chemotherapy cycle were more frequent in the placebo group (31%) than in the palifermin group (14%). Investigators reported lower mucositis scores and patients reported less severe symptoms with palifermin. There were no statistically significant differences in the incidence or severity of diarrhea or in overall survival between the groups. Overall, palifermin was safe and well tolerated. CONCLUSION: Palifermin administered at the indicated dosing regimen (40 microg/kg for 3 consecutive days) before chemotherapy was well tolerated and resulted in a statistically significant and clinically meaningful reduction in the incidence of WHO grade 2 or higher OM in patients with metastatic CRC.