Paul Wheatley-Price

Prospective validation of risk prediction indexes for acute and delayed chemotherapy-induced nausea and vomiting

BACKGROUND Despite the use of standardized anti-emetic guidelines, up to 20% of cancer patients suffer from moderate-to-severe chemotherapy-induced nausea and vomiting (cinv)-that is, grade 2 or greater according to the U.S. National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. We previously developed cycle-based prediction models and associated scoring systems for acute and delayed cinv. As part of the validation process, we prospectively evaluated the ability of the scoring systems to accurately identify patients deemed to be high risk for grade 2 or greater cinv. METHODS Patients who were receiving any chemotherapy for solid tumours and who consented to participate were provided with symptom diaries. Compliance to the diaries was enhanced by 24-hour and 5-day telephone callbacks after chemotherapy in every cycle. All patients received anti-emetic prophylaxis as prescribed by the treating physician. Before each cycle of chemotherapy, the acute and delayed cinv scoring systems were used to stratify patients into low- and high-risk groups. Logistic regression modelling was then applied to compare the risk for grade 2 or greater cinv between patients considered to be at high and at low risk. The external validity of each system was also assessed using an area under the receiver operating characteristic curve (auroc) analysis. RESULTS We collected cinv outcomes data from 95 patients during 181 cycles of chemotherapy. The incidence of grade 2 or greater acute and delayed cinv was 17.7% and 18.2% respectively. As previously identified, major predictors for grade 2 or greater cinv included younger patient age, platinum- or anthracycline-based chemotherapy, low alcohol consumption, earlier cycles of chemotherapy, previous history of morning sickness, and prior emetic episodes after chemotherapy. The acute and delayed scoring systems both had good predictive accuracy when applied to the external validation sample (acute-auroc: 0.69; 95% confidence interval: 0.59 to 0.79; delayed-auroc: 0.70; 95% confidence interval: 0.60 to 0.80). Patients identified by the scoring systems to be at high risk were 2.8 (p = 0.025) and 3.1 (p = 0.001) times more likely to develop grade 2 or greater acute and delayed cinv. CONCLUSIONS The present study demonstrates that our scoring systems are able to accurately identify patients at high risk for acute and delayed cinv. Application and planned continued refinement of the scoring systems will be an important means of patient-specific risk assessment that will allow for optimization of anti-emetic therapy.

Incidence and consequences of bone metastases in lung cancer patients.

Background Bone metastases (BM) are common in NSCLC patients. Despite some potential positive effects of bone-targeted therapies, their use in NSCLC is infrequent, which may relate to the overall poor prognosis of advanced lung cancer. We reviewed the literature to evaluate the incidence, consequences and use of bone-targeting agents in lung cancer patients with BM in both the trial and non-trial clinical setting. Methods Published prospective and retrospective papers investigating lung cancer and BM, in trial and non-trial settings, were identified and are discussed in this review. Results BM are common in patients with advanced lung cancer and often present symptomatically with pain and skeletal related events (SREs). Patients with high bone turnover marker levels, multiple BM, and history of pathological fractures have shorter overall survival. In randomized studies bone-targeted therapies reduced the risk of SREs and prolonged the time to first SRE. The use of bone-targeted agents may also be associated with a survival benefit. Conclusion BM are a common problem in advanced lung cancer. While the benefits of bone-targeted therapies have been demonstrated, their use is limited in non-trial populations. If better predictive markers of individual risk were available this might increase the appropriate use of bone-targeted agents.

Risk Model–Guided Antiemetic Prophylaxis vs Physician’s Choice in Patients Receiving Chemotherapy for Early-Stage Breast Cancer: A Randomized Clinical Trial

IMPORTANCE Despite multiple patient-centered factors being associated with the risk of chemotherapy-induced nausea and vomiting (CINV), these factors are rarely considered when making antiemetic recommendations. OBJECTIVE To compare risk model-guided (RMG) antiemetic prophylaxis with physicians choice (PC) in patients receiving chemotherapy for early-stage breast cancer. DESIGN, SETTING, AND PARTICIPANTS A randomized clinical trial of 324 patients with early-stage breast cancer undergoing chemotherapy (cyclophosphamide and an anthracycline) for the first time at 2 specialty cancer care centers in Ottawa from April 10, 2012, to September 2, 2014. Patients were randomized to either the RMG arm (n = 154) or the PC control arm (n = 170). Prior to each cycle of chemotherapy patients in the RMG group were categorized as low or high risk for CINV, and their antiemetic treatments were adjusted accordingly. INTERVENTIONS Patients considered to be at low risk received standard dexamethasone and a 5-HT3 antagonist, while those at high risk also received aprepitant with or without olanzapine, based on their risk level. The PC control group received antiemetic agents according to the treating physicians discretion. MAIN OUTCOMES AND MEASURES The primary end points were control of both nausea and vomiting in the acute posttreatment period (first 24 hours after therapy) and in the delayed posttreatment period (days 2-5 after therapy). RESULTS The total numbers of chemotherapy cycles delivered in the RMG and PC control groups were 497 and 551 respectively. In the acute period, significantly more patients in the RMG group reported no nausea (53.7% [95% CI, 49.2%-58.1%] vs 41.6% [95% CI, 37.4%-45.3%]; P < .001) and no vomiting (91.8% [95% CI, 89.0%-94.0%] vs 82.2% [95% CI, 78.8%-85.3%]; P < .001) compared with the PC control group. Similarly, significantly more patients in the RMG group reported no nausea (39.6% [95% CI, 35.3%-44.1%] vs 30.7% [95% CI, 26.8%-34.7%]; P = .01) and no vomiting (87.1% [95% CI, 83.8%-90.0%) vs 78.0% [95% CI, 74.3%-81.4%]; P < .001) in the delayed period respectively. CONCLUSIONS AND RELEVANCE In this trial, the RMG antiemetic prophylaxis led to improved control of acute and delayed CINV compared with physicians choice of therapy. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01913990.

The incidence and clinical impact of bone metastases in non-small cell lung cancer

INTRODUCTION Non-small cell lung cancer (NSCLC) is the leading global cause of cancer death. While bone metastases (BM) commonly cause morbidity, bone-targeted agent (BTA) use is variable. We investigated the incidence and impact of BM among unselected NSCLC patients. METHODS A retrospective chart review of all NSCLC patients seen at a single institution from January 2007 to January 2008 was performed. Various clinical and pathology data were collected. In BM patients, skeletal related events (SRE), interventions and outcomes were recorded. RESULTS We identified 383 patients; median age 68 (IQR 60-76); 54% female. Initially 156 patients (41%) were treated with curative intent of whom 91 subsequently relapsed; 227 (59%) were considered palliative from time of diagnosis, including 22 with early stage disease not amenable to radical therapy. Of 296 patients with advanced NSCLC, common metastatic sites were: lung/pleura (80%), mediastinal nodes (69%), bone (39%), brain (30%), and liver (24%). Of 118 patients with BM, 69 (59%) had ≥1 SREs (range 1-18). Common SREs were radiotherapy (63%), pathologic fractures (22%), spinal cord compression (6%) or surgery to bone (5%). Opioid analgesia was required in 69% of BM patients, only 6% of patients with BM received BTA. Overall survival (OS) in pts with mNSCLC was 7.3 months (IQR 3.1-20.5). Pts with BM had significantly shorter OS compared to those without BM (5.8 versus 10.2 months, p=0.03). CONCLUSIONS BM are common in patients with advanced NSCLC and associated with shorter survival. In this cohort, despite SREs occurred in many patients, BTA were rarely used.

Ribociclib plus endocrine therapy for premenopausal women with hormone-receptor-positive, advanced breast cancer (MONALEESA-7): a randomised phase 3 trial

BACKGROUND In MONALEESA-2, ribociclib plus letrozole showed improved progression-free survival compared with letrozole alone as first-line treatment for postmenopausal patients with hormone receptor (HR)-positive, HER2-negative, advanced breast cancer. MONALEESA-7 aimed to assess the efficacy and safety of ribociclib plus endocrine therapy in premenopausal women with advanced, HR-positive breast cancer. METHODS This phase 3, randomised, double-blind, placebo-controlled trial was done at 188 centres in 30 countries. Eligible patients were premenopausal women aged 18-59 years who had histologically or cytologically confirmed HR-positive, HER2-negative, advanced breast cancer; an Eastern Cooperative Oncology Group performance status of 0 or 1; measurable disease as per Response Evaluation Criteria in Solid Tumors version 1.1 criteria, or at least one predominantly lytic bone lesion; and had not received previous treatment with cyclin-dependent kinases 4 and 6 inhibitors. Endocrine therapy and chemotherapy in the adjuvant or neoadjuvant setting was permitted, as was up to one line of chemotherapy for advanced disease. Patients were randomly assigned (1:1) via interactive response technology to receive oral ribociclib (600 mg/day on a 3-weeks-on, 1-week-off schedule) or matching placebo with either oral tamoxifen (20 mg daily) or a non-steroidal aromatase inhibitor (letrozole 2·5 mg or anastrozole 1 mg, both oral, daily), all with goserelin (3·6 mg administered subcutaneously on day 1 of every 28-day cycle). Patients and investigators were masked to treatment assignment. Efficacy analyses were by intention to treat, and safety was assessed in all patients who received at least one dose of any study treatment. The primary endpoint was investigator-assessed progression-free survival. MONALEESA-7 is registered with ClinicalTrials.gov, NCT02278120 and is ongoing, but no longer enrolling patients. FINDINGS Between Dec 17, 2014, and Aug 1, 2016, 672 patients were randomly assigned: 335 to the ribociclib group and 337 to the placebo group. Per investigators assessment, median progression-free survival was 23·8 months (95% CI 19·2-not reached) in the ribociclib group compared with 13·0 months (11·0-16·4) in the placebo group (hazard ratio 0·55, 95% CI 0·44-0·69; p<0·0001). Grade 3 or 4 adverse events reported in more than 10% of patients in either group were neutropenia (203 [61%] of 335 patients in the ribociclib group and 12 [4%] of 337 in the placebo group) and leucopenia (48 [14%] and four [1%]). Serious adverse events occurred in 60 (18%) of 335 patients in the ribociclib group and 39 (12%) of 337 in the placebo group, of which 15 (4%) and six (2%), respectively, were attributed to the study regimen. 12 (4%) of 335 patients in the ribociclib group and ten (3%) of 337 in the placebo group discontinued treatment because of adverse events. No treatment-related deaths occurred. 11 deaths occurred (five [1%] in the ribociclib group and six [2%] in the placebo group) during or within 30 days after treatment, most of which were due to progression of the underlying breast cancer (three [1%] and six [2%]). The remaining two deaths in the ribociclib group were due to an intracranial haemorrhage in an anticoagulated patient, and a pre-existing wound haemorrhage in another patient. INTERPRETATION Ribociclib plus endocrine therapy improved progression-free survival compared with placebo plus endocrine therapy, and had a manageable safety profile in patients with premenopausal, HR-positive, HER2-negative, advanced breast cancer. The combination could represent a new first-line treatment option for these patients. FUNDING Novartis.

Palliative systemic therapy for advanced non-small cell lung cancer: Investigating disparities between patients who are treated versus those who are not

BACKGROUND Palliative systemic therapy (ST) in advanced non-small cell lung cancer (NSCLC) is associated with improved overall survival (OS) and quality of life, yet many patients remain untreated. We explored differences between patients who did and did not receive palliative ST in order to gain evidence to support and advocate for the untreated. METHODS We performed a retrospective analysis of newly diagnosed patients with advanced, incurable NSCLC seen as outpatients at our institution between 2009 and 2012. Demographics, treatment, and survival data were collected. RESULTS 528 patients were seen: 291 (55%) received palliative ST, while 237 (45%) received none. Demographics were as follows: Median age 67, 55% male, 50% ECOG performance status (PS) 0-1, 48% with weight loss. Untreated patients were older (median 71 vs. 64, p<0.01), less fit (PS 0-1 in 27% vs. 69%, p<0.01), and more likely to have lost weight (57% vs. 41%, p<0.01). Reasons for no treatment included poor PS (67%) and patient choice (23%). Median OS was shorter amongst untreated patients (3.9 vs. 10.7 months, HR 1.80 [95% CI 1.4-2.3], p<0.01). In multivariate analysis, not receiving ST was associated with shorter OS. CONCLUSION Unsurprisingly, untreated patients had poorer prognostic features and worse OS. However, it is concerning that, despite being seen in an active academic center, nearly half of all referred patients with advanced NSCLC received no anti-cancer treatment. Current research primarily seeks to improve outcomes in treated patients with good PS. This review suggests that this is an inappropriate allocation of research effort. Our research should be more equitably split between good and poor performance patient groups if we are to improve the survival of all patients with advanced NSCLC. Potential strategies include more rapid diagnosis prior to functional decline, and the development of therapies effective and tolerated in a sicker population.

Palliative chemotherapy in advanced colorectal cancer patients 80 years of age and older

BACKGROUND Colorectal cancer (crc) has a median diagnostic age of 68 years. Despite significant progress in chemotherapy (ctx) options, few data on outcomes or toxicity from ctx in patients 80 years of age and older are available. We investigated ctx in such patients with metastatic crc (mcrc), hypothesizing high rates of hospitalization and toxicity. METHODS A retrospective chart review identified patients 80 years of age and older with mcrc who initiated ctx between 2005-2010 at our institution. Patient demographics and ctx data were collected. Endpoints included rates of hospitalization, ctx discontinuation because of toxicity, and overall survival. RESULTS In 60 patients, ctx was initiated on 88 occasions. Median age in the cohort was 83 years; 52% were men; 72% lived with family; 53% had a modified Charlson comorbidity index of 2 or greater; and 31% were taking 6 or more prescription medications at baseline. At baseline, 33% of the patients were anemic (hemoglobin < 100 g/L), 36% had leukocytosis (white blood cells > 11×10(9)/L), and 48% had renal impairment (estimated glomerular filtration rate < 60 mL/min/1.73 m(2)). In 53%, ctx was given as first-line treatment. The initial ctx dose was adjusted in 67%, and capecitabine was the most common chemotherapeutic agent (45%). In 19 instances (22%), the patient was hospitalized during or within 30 days of ctx; in 26 instances (30%), the ctx was discontinued because of toxicity, and in 48 instances (55%), the patient required at least 1 dose reduction, omission, or delay. Median overall survival was 17.8 months (95% confidence interval: 14.3 to 20.8 months). CONCLUSIONS In the population 80 years of age and older, ctx for mcrc is feasible; however, most recipients will require dose adjustments, and a significant proportion will be hospitalized or stop ctx because of toxicity. Prospective research incorporating geriatric assessment tools is required to better select these older patients for ctx.

Factors influencing a specific pathologic diagnosis of non-small-cell lung carcinoma.

INTRODUCTION Historically, a non-small-cell lung carcinoma diagnosis, without pathologic subclassification, provided sufficient information to guide therapy. Evidence now demonstrates that pathologic subtype classification is central in selecting optimal treatment. This review aimed to identify factors associated with a specific pathologic diagnosis. METHODS All nonoperative cases of non-small-cell lung carcinoma (NSCLC) referred to the medical oncology divisions of the Ottawa Hospital Cancer Centre (2008) and Princess Margaret Hospital, Toronto (2007-2010) were identified. The charts were reviewed for demographics, diagnostic methods, and final diagnosis. Logistic regression was performed to identify variables associated with a specific diagnosis. RESULTS Of 739 patient records analyzed, 377 (51%) were men, 299 (40%) were aged over 70 years, and 510 (69%) had an Eastern Cooperative Oncology Group performance status of 0-2. Three hundred and eighty five (52%) of patients were diagnosed in a tertiary academic center. The lung primary was sampled in 503 (68%) of patients. Computed tomography-guided biopsy (n = 370, 50%) and bronchoscopy (n = 179, 24%) were the most common techniques. Four hundred and seventy seven (65%) of biopsies were cytologic specimens alone, and immunohistochemistry was performed in 337 (46%) of cases. The most common diagnoses were adenocarcinoma (n = 338, 46%), NSCLC not otherwise specified (n = 254, 34%), and squamous cell carcinoma (n = 115, 16%). Overall, 456 (62%) of patients received a specific pathologic diagnosis. Factors significantly associated with attaining a specific pathologic diagnosis were diagnosis outside an academic center (adjusted odds ratios [OR] 2.1 [95% CI, 1.41-3.14]; P = .0003), histologic laboratory samples (adjusted OR 1.58 [95% CI, 1.003-2.49]; P = .049), and immunohistochemical testing (adjusted OR 1.82 [95% CI, 1.25-2.70], P = .0021). CONCLUSIONS A significant minority of patients with NSCLC do not receive a specific pathologic diagnosis. In an era of individualized medicine, this may potentially impact optimal clinical management.

Treatment patterns and survival in patients with ALK-positive non-small-cell lung cancer: a Canadian retrospective study

BACKGROUND Crizotinib was the first agent approved for the treatment of anaplastic lymphoma kinase (ALK)-positive (+) non-small-cell lung cancer (nsclc), followed by ceritinib. However, patients eventually progress or develop resistance to crizotinib. With limited real-world data available, the objective of the present work was to evaluate treatment patterns and survival after crizotinib in patients with locally advanced or metastatic ALK+ nsclc in Canada. METHODS In this retrospective study at 6 oncology centres across Canada, medical records of patients with locally advanced or metastatic ALK+ nsclc were reviewed. Demographic and clinical characteristics, treatments, and outcomes data were abstracted. Analyses focused on patients who discontinued crizotinib treatment. RESULTS Of the 97 patients included, 9 were crizotinib-naïve, and 39 were still receiving crizotinib at study end. The 49 patients who discontinued crizotinib treatment were included in the analysis. Of those 49 patients, 43% received ceritinib at any time, 20% subsequently received systemic chemotherapy only (but never ceritinib), and 37% received no further treatment or died before receiving additional treatment. Median overall survival from crizotinib discontinuation was shorter in patients who did not receive ceritinib than in those who received ceritinib (1.7 months vs. 20.4 months, p < 0.001). In a multivariable analysis, factors associated with poorer survival included lack of additional therapies (particularly ceritinib), male sex, and younger age, but not smoking status; patients of Asian ethnicity showed a nonsignificant trend toward improved survival. CONCLUSIONS A substantial proportion of patients with ALK+ nsclc received no further treatment or died before receiving additional treatment after crizotinib. Treatment with systemic agents was associated with improved survival, with ceritinib use being associated with the longest survival.

Malignant Pleural Mesothelioma Outcomes in the Era of Combined Platinum and Folate Antimetabolite Chemotherapy

Introduction. Malignant pleural mesothelioma (MPM) is associated with a poor prognosis. Palliative platinum-based chemotherapy may help to improve symptoms and prolong life. Since 2004, the platinum is commonly partnered with a folate antimetabolite. We performed a review investigating if survival had significantly changed before and after the arrival of folate antimetabolites in clinical practice. Methods. All MPM patients from January 1991 to June 2012 were identified. Data collected included age, gender, asbestos exposure, presenting signs/symptoms, performance status, histology, stage, bloodwork, treatment modalities including chemotherapy, and date of death or last follow-up. The primary endpoint was overall survival. Cox models were applied to determine variables associated with survival. Results. There were 245 patients identified. Median overall survival for all patients was 9.4 months. After multivariate analysis, performance status, stage, histology, leucocytosis, and thrombophilia remained independently associated with survival. Among all patients who received chemotherapy, there was no difference in overall survival between the periods before and after folate antimetabolite approval: 14.2 versus 13.2 months (P = 0.35). Specifically receiving combined platinum-based/folate antimetabolite chemotherapy did not improve overall survival compared to all other chemotherapy regimens: 14.1 versus 13.6 months (P = 0.97). Conclusions. In this review, we did not observe an incremental improvement in overall survival after folate antimetabolites became available.