N. Bouganim

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

BACKGROUNDnDespite 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.nnnMETHODSnPatients 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.nnnRESULTSnWe 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.nnnCONCLUSIONSnThe 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.

Acquisition of metastatic tissue from patients with bone metastases from breast cancer

Biopsies of metastatic tissue are increasingly being performed. Bone is the most frequent site of metastasis in breast cancer patients, but bone remains technically challenging to biopsy. Difficulties with both tissue acquisition and techniques for analysis of hormone receptor status are well described. Bone biopsies can be carried out by either by standard posterior iliac crest bone marrow trephine/aspiration or CT-guided biopsy of a radiologically evident bone metastasis. The differential yield of these techniques is unknown. Results from three prospective studies of similar methodology were pooled. Patients underwent both an outpatient posterior iliac crest bone marrow trephine/aspiration and a CT-guided biopsy of a radiologically evident bone metastasis. Samples were assessed for the presence of malignant cells and where possible also for estrogen (ER) and progesterone receptor (PgR) expression.xa040 patients were enrolled. Bone marrow aspiration/trephine biopsy was completed in 39/40 (97.5%) and CT-guided biopsy was completed in 34/40 (85%) of patients. Sufficient tumor cells for hormone receptor analysis were available in 19/39 (48.8%) and 16/34 (47%) of and bone marrow aspiration/trephine and CT-guided biopsies, respectively. Significant discordance in ER and PgR between the primary and the bone metastasis was also seen. Nine patients had tissue available from both bone marrow and CT-guided bone biopsies. ER and PgR concordance between these sites was 100 and 78%, respectively. Performing studies on human bone metastases is technically challenging, with relatively low yields regardless of technique. Given resource issues and similar success rates when comparing both techniques, bone marrow examination may be utilized first and if inadequate tissue is obtained, CT-guided biopsies can then be used.

Optimising the use of bone-targeted agents in patients with metastatic cancers: a practical guide for medical oncologists

Bone metastases can be associated with a significant worsening of patient morbidity and mortality. Bisphosphonates have been extensively researched and shown to delay the onset and reduce the incidence of complications from bone metastases. The most commonly used bisphosphonates are intravenous pamidronate, intravenous ibandronate, intravenous zoledronic acid and oral/intravenous clodronate. Several bone-targeted agents with innovative mechanisms of action are currently being developed. These include receptor activator of nuclear factor-kB ligand (RANKL) inhibitors, CCR1 inhibitors, Src inhibitors, DKK1-neutralising antibodies, activin antagonists and endothelin-1 inhibitors. In an era of individualised medicine, oncologists are being faced with an increasing number of questions when dealing with bone-targeted agents. These questions not only include the choice of which drug to use (i.e. bisphosphonates or RANKL inhibitor) but also the best treatment strategy to use. This review will provide medical oncologists with a practical guide to the use of bone-targeted agents.

Platinum-based chemotherapy in triple-negative advanced breast cancer

The purpose of this study was to evaluate the efficacy of platinum-based chemotherapy (PBC) versus conventional non-PBC regimens in a metastatic triple-negative breast cancer (TNBC)xa0setting. We reviewed the electronic patient records of patients with confirmed metastatic TNBC at four major cancer centres in Canada. All patients were allocated into two groups based on type of chemotherapy received (PBC vs. non-PBC) and line of treatment (first-, second-, or third-line). The primary objective of this study was to evaluate the efficacy of PBC in metastatic TNBC in terms of median duration of overall survival (OS) from diagnosis of distant metastatic disease and compare it with the efficacy of conventional non-platinum-based chemotherapy in metastatic TNBC after controlling for known prognostic factors. A total of 153 metastatic TNBC patients were identified, 58 treated with PBC and 95 with non-PBC. The median time in first-line PBC versus non-PBC was not different between the two groups (2 vs. 2 months, pxa0=xa00.9), the median time on treatment in second and third-line therapy was longer for the PBC group compared to the conventional treated group (4 vs. 1 months, pxa0=xa00.004; 4 vs. 0.5 months, pxa0=xa00.004, respectively). Patients who received PBC had a longer OS compared to those managed conventionally (14.5 vs. 10 months, pxa0=xa00.041). This study evaluates the survival outcomes in a homogenous group of TNBC metastatic patients treated with or without PBC. Our results confirmed our hypothesis of a better OS among PBC-treated TNBC patients compared to conventionally managed TNBC patients. Currently ongoing Phase III trials assessing the benefit of PBC versus other chemotherapeutic regimens in advanced TNBC will help define the role of these agents for the management of this breast cancer subtype.

A phase II, multicentre trial evaluating the efficacy of de-escalated bisphosphonate therapy in metastatic breast cancer patients at low-risk of skeletal-related events

Abstract The optimal frequency of intravenous (IV) bisphosphonate administration is unclear. We thus performed a study evaluating the effects of switching from 3–4 to 12 weekly therapy in patients with biochemically defined low-risk bone metastases. Patients with serum C-telopeptide (CTx) levels ≤600xa0ng/L after ≥3xa0months of 3–4 weekly IV pamidronate were switched to 12 weekly therapy for 48xa0weeks. Primary endpoint was the proportion of patients maintaining CTx levels in the lower-risk range. All endpoints (serum CTx and bone-specific alkaline phosphatase (BSAP), skeletal-related events (SREs) and self-reported pain) were measured at baseline, 6, 12, 24, 36 and 48xa0weeks. Treatment failure was defined as biochemical failure (CTxxa0>xa0600xa0ng/L) or a SRE. Exploratory biomarkers including; serum TGF-β, activin-A, bone sialoprotein (BSP), procollagen type 1 N-terminal propeptide and urinary N-telopeptide (NTx) were assessed at baseline as predictors for failure to complete treatment. Seventy-one patients accrued and 43 (61xa0%) completed 48xa0weeks of de-escalated therapy. Reasons for failure to complete treatment included; biochemical failure (CTxxa0>xa0600xa0ng/L) (nxa0=xa010, 14.1xa0%), on-study SRE (nxa0=xa09, 12.7xa0%), disease progression (nxa0=xa07, 9.9xa0% including death from disease [nxa0=xa01, 1.4xa0%]) or patient choice (nxa0=xa02, 2.8xa0%). Elevated baseline levels of CTx, BSAP, NTx and BSP were associated with treatment failure. The majority of patients in this biochemically defined low-risk population could switch from 3–4 weekly to 12 weekly bisphosphonate therapy with no effect on CTx levels or SREs during the 48xa0week study. Larger trials are required to assess the roles of biomarkers as predictors of adequacy of de-escalated therapy.

Do alternative methods of measuring tumor size, including consideration of multicentric/multifocal disease, enhance prognostic information beyond TNM staging in women with early stage breast cancer: an analysis of the NCIC CTG MA.5 and MA.12 clinical trials

The AJCC staging criteria consider tumor size to be the largest dimension of largest tumor. Some case series suggest using summation of all tumor dimensions in patients with multicentric/multifocal (MC/MF) disease. We used data from NCIC CTG MA.5 and MA.12 clinical trials to examine alternative methods of assessing tumor size on breast-cancer-free-interval (BCFI). The 710 MA.5 pre-/peri-menopausal node positive and 672 MA.12 pre-menopausal node-negative/-positive patients have 10-year median follow-up. All patients received adjuvant chemotherapy. Tumors were centrally reviewed for grade, hormone receptor, and HER2 status. Continuous pathologic tumor size was: (1) largest dimension of largest tumor (cm); (2) tumor area (cm2); (3) volume of tumor (cm3); (4) with MC/MF disease, summation of (1)–(3) for up to 3 foci. We examined univariate and multivariate effects of tumor size on BCFI utilizing (un)stratified Cox regression and the Wald test statistic. In univariate analysis, larger tumor dimension was significantly associated with worse BFCI in node positive patients: pxa0<xa00.0001 for MA.5; pxa0=xa00.01 for MA.12. In MA.5 multivariate analysis, larger summation of largest tumor dimensions was associated with worse BCFI (pxa0=xa00.0003), while larger single dimension was associated with worse BCFI (pxa0=xa00.02) for MA.12. Presence of MC/MF and other tumor size measurements were not associated (pxa0>xa00.05) with BFCI. While physicians could consider the largest diameter of the largest focus of disease or the sum of the largest diameters of all foci in their T-stage determination, it appears that the current method of T-staging offers equivalent determinations of prognosis.

Use and delivery of granulocyte colony-stimulating factor in breast cancer patients receiving neoadjuvant or adjuvant chemotherapy-single-centre experience.

BACKGROUNDnUse of granulocyte colony-stimulating factor (g-csf) as primary prophylaxis against chemotherapy-induced neutropenia has significant cost implications. We examined use of g-csf for early-stage breast cancer patients at our centre. The study also examined the pattern of nurse-led patient teaching with respect to drug self-administration.nnnMETHODSnPatients who received g-csf between November 2009 and October 2010 were identified from pharmacy records. After consent had been obtained, electronic charts were examined to extract data on chemotherapy and use of g-csf. Patients were contacted by telephone to obtain information on the utilization of home-care nursing visits for g-csf administration.nnnRESULTSnThe study analyzed 36 patients. Median age was 58 years (range: 31-78 years). Of the 36 patients, 30 (83%) had received adjuvant treatment, and 6 (17%), neoadjuvant treatment. Most patients (71%) received 10 days (range: 7-10 days) of filgrastim. Of the 36 patients, 29 (81%) received g-csf as primary prophylaxis. In 90% of those patients, primary prophylaxis commenced with the taxane component of treatment. Of the 36 patients, 7 (19%) received g-csf after neutropenia, including 2 who had febrile neutropenia. In 96% of the patients, injections were received at home with the help of a nurse; those patients were subsequently taught self-injection techniques. The median number of nursing visits was 2 (range: 1-3 visits). Most patients were satisfied with the home care and g-csf teaching they received.nnnCONCLUSIONSnMost of the g-csf used in breast cancer treatment during the study period was given for primary prophylaxis. A major reason for the decision to use g-csf appears to have been physician-perceived risk of febrile neutropenia. Delivery of g-csf by home-care nurses was well received by patients.

A randomized, double-blind, phase II, exploratory trial evaluating the palliative benefit of either continuing pamidronate or switching to zoledronic acid in patients with high-risk bone metastases from breast cancer

Previous studies suggest switching from pamidronate to a more potent bone-targeted agent is associated with biomarker and palliative response in breast cancer patients with bone metastases. Until now, this has not been addressed in a double-blind, randomized trial. Breast cancer patients with high-risk bone metastases, despite >3xa0months of pamidronate, were randomized to either continue pamidronate or switch to zoledronic acid every 4xa0weeks for 12xa0weeks. Primary outcome was the proportion of patients achieving a fall in serum C-telopeptide (sCTx) at 12xa0weeks. Secondary outcomes included difference in mean sCTx, pain scores, quality of life, toxicity, and skeletal-related events (SREs). Seventy-three patients entered the study; median age 61xa0years (range 37–87). Proportion of patients achieving a fall in sCTx over the 12-week evaluation period was 26/32 (81xa0%) with zoledronic acid and 18/29 (62xa0%) with pamidronate (pxa0=xa00.095). Mean decrease in sCTx (mean difference between groupsxa0=xa050xa0ng/L, 95xa0% CI 18–84; pxa0=xa00.003) was significantly greater in patients who received zoledronic acid. Quality of life, pain scores, toxicity, and frequency of new SREs were comparable between the two arms. While a switch from pamidronate to zoledronic acid resulted in reduction in mean sCTx, there were no significant differences between the arms for proportion of patients achieving a reduction in sCTx, quality of life, pain scores, toxicity or SREs. Given the lack of palliative improvement, the current data do not support a switching strategy.

Dual Blockade of HER2 — Twice as Good or Twice as Toxic?

With about 20% of breast cancers overexpressing HER2, the implementation of trastuzumab and, more recently, lapatinib has revolutionised the care of these patients. Despite these successes, de novo and acquired resistance to these agents represent significant barriers that need to be overcome if further progress is to be achieved. Given that resistance can involve interplay between different members of the HER family multi-targeted inhibition of HER receptors represents an interesting therapeutic strategy. To date, clinical trials have shown that a number of targeted drugs can be combined with trastuzumab and lead to improved overall response rates and potentially also survival. However, such progress leads to an increased burden of toxicity. This review will discuss the mechanisms behind HER2 resistance, the preclinical basis for combining different agents with trastuzumab and the available results from clinical studies evaluating these combinations.