Purpose
Prior to publication of the Clavien-Dindo classification in 2004, there were no grading definitions for surgical complications in either clinical practice or surgical trials. This report ...establishes supplementary criteria for this classification to standardize the evaluation of postoperative complications in clinical trials.
Methods
The Japan Clinical Oncology Group (JCOG) commissioned a committee. Members from nine surgical study groups (gastric, esophageal, colorectal, lung, breast, gynecologic, urologic, bone and soft tissue, and brain) specified postoperative complications experienced commonly in their fields and defined more detailed grading criteria for each complication in accordance with the general grading rules of the Clavien-Dindo classification.
Results
We listed 72 surgical complications experienced commonly in surgical trials, focusing on 17 gastroenterologic complications, 13 infectious complications, six thoracic complications, and several other complications. The grading criteria were defined simply and were optimized for surgical complications.
Conclusions
The JCOG postoperative complications criteria (JCOG PC criteria) aim to standardize the terms used to define adverse events (AEs) and provide detailed grading guidelines based on the Clavien-Dindo classification. We believe that the JCOG PC criteria will allow for more precise comparisons of the frequency of postoperative complications among trials across many different surgical fields.
Olaparib is an oral poly(adenosine diphosphate-ribose) polymerase inhibitor that has promising antitumor activity in patients with metastatic breast cancer and a germline BRCA mutation.
We conducted ...a randomized, open-label, phase 3 trial in which olaparib monotherapy was compared with standard therapy in patients with a germline BRCA mutation and human epidermal growth factor receptor type 2 (HER2)-negative metastatic breast cancer who had received no more than two previous chemotherapy regimens for metastatic disease. Patients were randomly assigned, in a 2:1 ratio, to receive olaparib tablets (300 mg twice daily) or standard therapy with single-agent chemotherapy of the physician's choice (capecitabine, eribulin, or vinorelbine in 21-day cycles). The primary end point was progression-free survival, which was assessed by blinded independent central review and was analyzed on an intention-to-treat basis.
Of the 302 patients who underwent randomization, 205 were assigned to receive olaparib and 97 were assigned to receive standard therapy. Median progression-free survival was significantly longer in the olaparib group than in the standard-therapy group (7.0 months vs. 4.2 months; hazard ratio for disease progression or death, 0.58; 95% confidence interval, 0.43 to 0.80; P<0.001). The response rate was 59.9% in the olaparib group and 28.8% in the standard-therapy group. The rate of grade 3 or higher adverse events was 36.6% in the olaparib group and 50.5% in the standard-therapy group, and the rate of treatment discontinuation due to toxic effects was 4.9% and 7.7%, respectively.
Among patients with HER2-negative metastatic breast cancer and a germline BRCA mutation, olaparib monotherapy provided a significant benefit over standard therapy; median progression-free survival was 2.8 months longer and the risk of disease progression or death was 42% lower with olaparib monotherapy than with standard therapy. (Funded by AstraZeneca; OlympiAD ClinicalTrials.gov number, NCT02000622 .).
The cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor palbociclib, in combination with fulvestrant therapy, prolongs progression-free survival among patients with hormone-receptor-positive, human ...epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer. We report the results of a prespecified analysis of overall survival.
We randomly assigned patients with hormone-receptor-positive, HER2-negative advanced breast cancer who had progression or relapse during previous endocrine therapy to receive palbociclib plus fulvestrant or placebo plus fulvestrant. We analyzed overall survival; the effect of palbociclib according to the prespecified stratification factors of presence or absence of sensitivity to endocrine therapy, presence or absence of visceral metastatic disease, and menopausal status; the efficacy of subsequent therapies after disease progression; and safety.
Among 521 patients who underwent randomization, the median overall survival was 34.9 months (95% confidence interval CI, 28.8 to 40.0) in the palbociclib-fulvestrant group and 28.0 months (95% CI, 23.6 to 34.6) in the placebo-fulvestrant group (hazard ratio for death, 0.81; 95% CI, 0.64 to 1.03; P=0.09; absolute difference, 6.9 months). CDK4/6 inhibitor treatment after the completion of the trial regimen occurred in 16% of the patients in the placebo-fulvestrant group. Among 410 patients with sensitivity to previous endocrine therapy, the median overall survival was 39.7 months (95% CI, 34.8 to 45.7) in the palbociclib-fulvestrant group and 29.7 months (95% CI, 23.8 to 37.9) in the placebo-fulvestrant group (hazard ratio, 0.72; 95% CI, 0.55 to 0.94; absolute difference, 10.0 months). The median duration of subsequent therapy was similar in the two groups, and the median time to the receipt of chemotherapy was 17.6 months in the palbociclib-fulvestrant group, as compared with 8.8 months in the placebo-fulvestrant group (hazard ratio, 0.58; 95% CI, 0.47 to 0.73; P<0.001). No new safety signals were observed with 44.8 months of follow-up.
Among patients with hormone-receptor-positive, HER2-negative advanced breast cancer who had sensitivity to previous endocrine therapy, treatment with palbociclib-fulvestrant resulted in longer overall survival than treatment with placebo-fulvestrant. The differences in overall survival in the entire trial group were not significant. (Funded by Pfizer; PALOMA-3 ClinicalTrials.gov number, NCT01942135 .).
Patients who have residual invasive carcinoma after the receipt of neoadjuvant chemotherapy for human epidermal growth factor receptor 2 (HER2)-negative breast cancer have poor prognoses. The benefit ...of adjuvant chemotherapy in these patients remains unclear.
We randomly assigned 910 patients with HER2-negative residual invasive breast cancer after neoadjuvant chemotherapy (containing anthracycline, taxane, or both) to receive standard postsurgical treatment either with capecitabine or without (control). The primary end point was disease-free survival. Secondary end points included overall survival.
The result of the prespecified interim analysis met the primary end point, so this trial was terminated early. The final analysis showed that disease-free survival was longer in the capecitabine group than in the control group (74.1% vs. 67.6% of the patients were alive and free from recurrence or second cancer at 5 years; hazard ratio for recurrence, second cancer, or death, 0.70; 95% confidence interval CI, 0.53 to 0.92; P=0.01). Overall survival was longer in the capecitabine group than in the control group (89.2% vs. 83.6% of the patients were alive at 5 years; hazard ratio for death, 0.59; 95% CI, 0.39 to 0.90; P=0.01). Among patients with triple-negative disease, the rate of disease-free survival was 69.8% in the capecitabine group versus 56.1% in the control group (hazard ratio for recurrence, second cancer, or death, 0.58; 95% CI, 0.39 to 0.87), and the overall survival rate was 78.8% versus 70.3% (hazard ratio for death, 0.52; 95% CI, 0.30 to 0.90). The hand-foot syndrome, the most common adverse reaction to capecitabine, occurred in 73.4% of the patients in the capecitabine group.
After standard neoadjuvant chemotherapy containing anthracycline, taxane, or both, the addition of adjuvant capecitabine therapy was safe and effective in prolonging disease-free survival and overall survival among patients with HER2-negative breast cancer who had residual invasive disease on pathological testing. (Funded by the Advanced Clinical Research Organization and the Japan Breast Cancer Research Group; CREATE-X UMIN Clinical Trials Registry number, UMIN000000843 .).
Summary Background In the PALOMA-3 study, the combination of the CDK4 and CDK6 inhibitor palbociclib and fulvestrant was associated with significant improvements in progression-free survival compared ...with fulvestrant plus placebo in patients with metastatic breast cancer. Identification of patients most suitable for the addition of palbociclib to endocrine therapy after tumour recurrence is crucial for treatment optimisation in metastatic breast cancer. We aimed to confirm our earlier findings with this extended follow-up and show our results for subgroup and biomarker analyses. Methods In this multicentre, double-blind, randomised phase 3 study, women aged 18 years or older with hormone-receptor-positive, HER2-negative metastatic breast cancer that had progressed on previous endocrine therapy were stratified by sensitivity to previous hormonal therapy, menopausal status, and presence of visceral metastasis at 144 centres in 17 countries. Eligible patients—ie, any menopausal status, Eastern Cooperative Oncology Group performance status 0–1, measurable disease or bone disease only, and disease relapse or progression after previous endocrine therapy for advanced disease during treatment or within 12 months of completion of adjuvant therapy—were randomly assigned (2:1) via a centralised interactive web-based and voice-based randomisation system to receive oral palbociclib (125 mg daily for 3 weeks followed by a week off over 28-day cycles) plus 500 mg fulvestrant (intramuscular injection on days 1 and 15 of cycle 1; then on day 1 of subsequent 28-day cycles) or placebo plus fulvestrant. The primary endpoint was investigator-assessed progression-free survival. Analysis was by intention to treat. We also assessed endocrine therapy resistance by clinical parameters, quantitative hormone-receptor expression, and tumour PIK3CA mutational status in circulating DNA at baseline. This study is registered with ClinicalTrials.gov , NCT01942135. Findings Between Oct 7, 2013, and Aug 26, 2014, 521 patients were randomly assigned, 347 to fulvestrant plus palbociclib and 174 to fulvestrant plus placebo. Study enrolment is closed and overall survival follow-up is in progress. By March 16, 2015, 259 progression-free-survival events had occurred (145 in the fulvestrant plus palbociclib group and 114 in the fulvestrant plus placebo group); median follow-up was 8·9 months (IQR 8·7–9·2). Median progression-free survival was 9·5 months (95% CI 9·2–11·0) in the fulvestrant plus palbociclib group and 4·6 months (3·5–5·6) in the fulvestrant plus placebo group (hazard ratio 0·46, 95% CI 0·36–0·59, p<0·0001). Grade 3 or 4 adverse events occurred in 251 (73%) of 345 patients in the fulvestrant plus palbociclib group and 38 (22%) of 172 patients in the fulvestrant plus placebo group. The most common grade 3 or 4 adverse events were neutropenia (223 65% in the fulvestrant plus palbociclib group and one 1% in the fulvestrant plus placebo group), anaemia (ten 3% and three 2%), and leucopenia (95 28% and two 1%). Serious adverse events (all causalities) occurred in 44 patients (13%) of 345 in the fulvestrant plus palbociclib group and 30 (17%) of 172 patients in the fulvestrant plus placebo group. PIK3CA mutation was detected in the plasma DNA of 129 (33%) of 395 patients for whom these data were available. Neither PIK3CA status nor hormone-receptor expression level significantly affected treatment response. Interpretation Fulvestrant plus palbociclib was associated with significant and consistent improvement in progression-free survival compared with fulvestrant plus placebo, irrespective of the degree of endocrine resistance, hormone-receptor expression level, and PIK3CA mutational status. The combination could be considered as a therapeutic option for patients with recurrent hormone-receptor-positive, HER2-negative metastatic breast cancer that has progressed on previous endocrine therapy. Funding Pfizer.
Summary Background Phosphatidylinositol 3-kinase (PI3K) pathway activation is a hallmark of endocrine therapy-resistant, hormone receptor-positive breast cancer. This phase 3 study assessed the ...efficacy of the pan-PI3K inhibitor buparlisib plus fulvestrant in patients with advanced breast cancer, including an evaluation of the PI3K pathway activation status as a biomarker for clinical benefit. Methods The BELLE-2 trial was a randomised, double-blind, placebo-controlled, multicentre study. Postmenopausal women aged 18 years or older with histologically confirmed, hormone receptor-positive and human epidermal growth factor (HER2)-negative inoperable locally advanced or metastatic breast cancer whose disease had progressed on or after aromatase inhibitor treatment and had received up to one previous line of chemotherapy for advanced disease were included. Eligible patients were randomly assigned (1:1) using interactive voice response technology (block size of 6) on day 15 of cycle 1 to receive oral buparlisib (100 mg/day) or matching placebo, starting on day 15 of cycle 1, plus intramuscular fulvestrant (500 mg) on days 1 and 15 of cycle 1, and on day 1 of subsequent 28-day cycles. Patients were assigned randomisation numbers with a validated interactive response technology; these numbers were linked to different treatment groups which in turn were linked to treatment numbers. PI3K status in tumour tissue was determined via central laboratory during a 14-day run-in phase. Randomisation was stratified by PI3K pathway activation status (activated vs non-activated vs and unknown) and visceral disease status (present vs absent). Patients, investigators, local radiologists, study team, and anyone involved in the study were masked to the identity of the treatment until unblinding. The primary endpoints were progression-free survival by local investigator assessment per Response Evaluation Criteria In Solid Tumors (version 1.1) in the total population, in patients with known (activated or non-activated) PI3K pathway status, and in PI3K pathway-activated patients. Efficacy analyses were done in the intention-to-treat population. Safety was analysed in all patients who received at least one dose of study drug and had at least one post-baseline safety assessment according to the treatment they received. This trial is registered with ClinicalTrials.gov , number NCT01610284 , and is currently ongoing but not recruiting participants. Findings Between Sept 7, 2012, and Sept 10, 2014, 1147 patients from 267 centres in 29 countries were randomly assigned to receive buparlisib (n=576) or placebo plus fulvestrant (n=571). In the total patient population (n=1147), median progression-free survival was 6·9 months (95% CI 6·8–7·8) in the buparlisib group versus 5·0 months (4·0–5·2) in the placebo group (hazard ratio HR 0·78 95% CI 0·67–0·89; one-sided p=0·00021). In patients with known PI3K status (n=851), median progression-free survival was 6·8 months (95% CI 5·0–7·0) in the buparlisib group vs 4·5 months (3·3–5·0) in the placebo group (HR 0·80 95% CI 0·68–0·94; one-sided p=0·0033). In PI3K pathway-activated patients (n=372), median progression-free survival was 6·8 months (95% CI 4·9–7·1) in the buparlisib group versus 4·0 months (3·1–5·2) in the placebo group (HR 0·76 0·60–0·97, one-sided p=0·014). The most common grade 3–4 adverse events in the buparlisib group versus the placebo group were increased alanine aminotransferase (146 25% of 573 patients vs six 1% of 570), increased aspartate aminotransferase (103 18% vs 16 3%), hyperglycaemia (88 15% vs one <1%), and rash (45 8% vs none). Serious adverse events were reported in 134 (23%) of 573 patients in the buparlisib group compared with 90 16% of 570 patients in the placebo group; the most common serious adverse events (affecting ≥2% of patients) were increased alanine aminotransferase (17 3% of 573 vs one <1% of 570) and increased aspartate aminotransferase (14 2% vs one <1%). No treatment-related deaths occurred. Interpretation The results from this study show that PI3K inhibition combined with endocrine therapy is effective in postmenopausal women with endocrine-resistant, hormone receptor-positive and HER2-negative advanced breast cancer. Use of more selective PI3K inhibitors, such as α-specific PI3K inhibitor, is warranted to further improve safety and benefit in this setting. No further studies are being pursued because of the toxicity associated with this combination. Funding Novartis Pharmaceuticals Corporation.
Summary Background Neratinib, an irreversible tyrosine-kinase inhibitor of HER1, HER2, and HER4, has clinical activity in patients with HER2-positive metastatic breast cancer. We aimed to investigate ...the efficacy and safety of 12 months of neratinib after trastuzumab-based adjuvant therapy in patients with early-stage HER2-positive breast cancer. Methods We did this multicentre, randomised, double-blind, placebo-controlled, phase 3 trial at 495 centres in Europe, Asia, Australia, New Zealand, and North and South America. Eligible women (aged ≥18 years, or ≥20 years in Japan) had stage 1–3 HER2-positive breast cancer and had completed neoadjuvant and adjuvant trastuzumab therapy up to 2 years before randomisation. Inclusion criteria were amended on Feb 25, 2010, to include patients with stage 2–3 HER2-positive breast cancer who had completed trastuzumab therapy up to 1 year previously. Patients were randomly assigned (1:1) to receive oral neratinib 240 mg per day or matching placebo. The randomisation sequence was generated with permuted blocks stratified by hormone receptor status (hormone receptor-positive oestrogen or progesterone receptor-positive or both vs hormone receptor-negative oestrogen and progesterone receptor-negative), nodal status (0, 1–3, or ≥4), and trastuzumab adjuvant regimen (sequentially vs concurrently with chemotherapy), then implemented centrally via an interactive voice and web-response system. Patients, investigators, and trial sponsors were masked to treatment allocation. The primary outcome was invasive disease-free survival, as defined in the original protocol, at 2 years after randomisation. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov , number NCT00878709. Findings Between July 9, 2009, and Oct 24, 2011, we randomly assigned 2840 women to receive neratinib (n=1420) or placebo (n=1420). Median follow-up time was 24 months (IQR 20–25) in the neratinib group and 24 months (22–25) in the placebo group. At 2 year follow-up, 70 invasive disease-free survival events had occurred in patients in the neratinib group versus 109 events in those in the placebo group (stratified hazard ratio 0·67, 95% CI 0·50–0·91; p=0·0091). The 2-year invasive disease-free survival rate was 93·9% (95% CI 92·4–95·2) in the neratinib group and 91·6% (90·0–93·0) in the placebo group. The most common grade 3–4 adverse events in patients in the neratinib group were diarrhoea (grade 3, n=561 40% and grade 4, n=1 <1% vs grade 3, n=23 2% in the placebo group), vomiting (grade 3, n=47 3% vs n=5 <1%), and nausea (grade 3, n=26 2% vs n=2 <1%). QT prolongation occurred in 49 (3%) patients given neratinib and 93 (7%) patients given placebo, and decreases in left ventricular ejection fraction (≥grade 2) in 19 (1%) and 15 (1%) patients, respectively. We recorded serious adverse events in 103 (7%) patients in the neratinib group and 85 (6%) patients in the placebo group. Seven (<1%) deaths (four patients in the neratinib group and three patients in the placebo group) unrelated to disease progression occurred after study drug discontinuation. The causes of death in the neratinib group were unknown (n=2), a second primary brain tumour (n=1), and acute myeloid leukaemia (n=1), and in the placebo group were a brain haemorrhage (n=1), myocardial infarction (n=1), and gastric cancer (n=1). None of the deaths were attributed to study treatment in either group. Interpretation Neratinib for 12 months significantly improved 2-year invasive disease-free survival when given after chemotherapy and trastuzumab-based adjuvant therapy to women with HER2-positive breast cancer. Longer follow-up is needed to ensure that the improvement in breast cancer outcome is maintained. Funding Wyeth, Pfizer, Puma Biotechnology.
Breast cancer is the most common type of cancer among women worldwide and in Japan. The majority of breast cancers are hormone receptor–positive (HR+)/human epidermal growth factor receptor ...2–negative (HER2‒), and endocrine therapy is an effective therapy for this type of breast cancer. However, recent substantial advances have been made in the management of HR+/HER2‒ advanced breast cancer (ABC) with the advent of targeted therapies, such as cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, resulting in significant improvements in survival outcomes versus endocrine therapy alone. To evaluate the optimal use of palbociclib, a CDK4/6 inhibitor, in HR+/HER2– ABC, this review summarizes clinical trial and real-world data for palbociclib. In addition, current biomarker studies in palbociclib clinical research are reviewed. In Japanese patients, palbociclib was shown to be effective with a manageable safety profile, although differences were observed in the frequency of adverse event and dosing parameters. Current evidence supporting palbociclib as a first-line treatment strategy for patients with HR+/HER2‒ ABC in Asia, and specifically japan, is also discussed.
Summary Background Disease progression in patients with HER2-positive breast cancer receiving trastuzumab might be associated with activation of the PI3K/Akt/mTOR intracellular signalling pathway. We ...aimed to assess whether the addition of the mTOR inhibitor everolimus to trastuzumab might restore sensitivity to trastuzumab. Methods In this randomised, double-blind, placebo-controlled, phase 3 trial, we recruited women with HER2-positive, trastuzumab-resistant, advanced breast carcinoma who had previously received taxane therapy. Eligible patients were randomly assigned (1:1) using a central patient screening and randomisation system to daily everolimus (5 mg/day) plus weekly trastuzumab (2 mg/kg) and vinorelbine (25 mg/m2 ) or to placebo plus trastuzumab plus vinorelbine, in 3-week cycles, stratified by previous lapatinib use. The primary endpoint was progression-free survival (PFS) by local assessment in the intention-to-treat population. We report the final analysis for PFS; overall survival follow-up is still in progress. This trial is registered with ClinicalTrials.gov , number NCT01007942. Findings Between Oct 26, 2009, and May 23, 2012, 569 patients were randomly assigned to everolimus (n=284) or placebo (n=285). Median follow-up at the time of analysis was 20·2 months (IQR 15·0–27·1). Median PFS was 7·00 months (95% CI 6·74–8·18) with everolimus and 5·78 months (5·49–6·90) with placebo (hazard ratio 0·78 95% CI 0·65–0·95; p=0·0067). The most common grade 3–4 adverse events were neutropenia (204 73% of 280 patients in the everolimus group vs 175 62% of 282 patients in the placebo group), leucopenia (106 38% vs 82 29%), anaemia (53 19% vs 17 6%), febrile neutropenia (44 16% vs ten 4%), stomatitis (37 13% vs four 1%), and fatigue (34 12% vs 11 4%). Serious adverse events were reported in 117 (42%) patients in the everolimus group and 55 (20%) in the placebo group; two on-treatment deaths due to adverse events occurred in each group. Interpretation The addition of everolimus to trastuzumab plus vinorelbine significantly prolongs PFS in patients with trastuzumab-resistant and taxane-pretreated, HER2-positive, advanced breast cancer. The clinical benefit should be considered in the context of the adverse event profile in this population. Funding Novartis Pharmaceuticals Corporation.
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