Safety of trastuzumab after trastuzumab emtansine-induced nodular regenerative hyperplasia: A case report.

INTRODUCTION: Trastuzumab emtansine is an antibody-drug conjugate targeting the human epidermal growth factor receptor 2 use in recurrent metastatic breast cancer. Cases of trastuzumab emtansine-induced nodular regenerative hyperplasia are often reported as overt noncirrhotic portal hypertension with ascites and variceal bleeding. CASE REPORT: We report the case of a 61-year-old woman who present multiple stellate angiomas with gradual increased liver transaminases and reduced platelet count during a 27-months course on trastuzumab emtansine therapy for recurrent metastatic breast cancer. After the nodular regenerative hyperplasia was histologically confirmed, the trastuzumab emtansine was stopped. After two months, trastuzumab was restarted together with exemestane. During trastuzumab therapy, the patient had a normalization of liver transaminases, platelet count and a gradual improvement of her stellate angiomas. Trastuzumab was continued for 15 months without any reoccurrence of nodular regenerative hyperplasia. MANAGEMENT AND OUTCOME: Nodular regenerative hyperplasia should be suspected after one year of trastuzumab emtansine treatment in patients with signs of portal hypertension without cirrhosis. Definitive cessation of trastuzumab emtansine is required after a diagnosis of nodular regenerative hyperplasia and complete resolution of symptoms generally takes several months. DISCUSSION: Based on fundamental studies, nodular regenerative hyperplasia is probably caused by the emtansine (DM1) part of the trastuzumab emtansine. It is still unclear if trastuzumab therapy can be reintroduced after nodular regenerative hyperplasia induced by trastuzumab emtansine, depriving the patient of a HER2-targeted therapy. Only one case reported having given trastuzumab in this situation over one month. In our case, trastuzumab was reintroduced without any complications for a long extent following TDM1-associated nodular regenerative hyperplasia.

Ultimate journey of the terminally ill: Ways and pathways of hope.

OBJECTIVE: To better understand the role of hope among terminally ill cancer patients. DESIGN: Qualitative analysis. SETTING: A tertiary specialized cancer centre in Canada. PARTICIPANTS: Cancer patients in palliative care with an estimated remaining life expectancy of 12 months or less (N = 12) and their loved ones (N = 12) and treating physicians (N = 12). METHODS: Each patient underwent up to 3 interviews and identified a loved one who participated in 1 interview. Treating physicians were also interviewed. All interviews were fully transcribed and analyzed by at least 2 investigators. Interviews were collected until saturation occurred. MAIN FINDINGS: Seven attributes describe the experiences of palliative cancer patients and their caregivers: hope as an irrational phenomenon that is a deeply rooted, affect-based response to adversity; initial hope for miraculous healing; hope as a phenomenon that changes over time, evolving in different ways depending on circumstances; hope for prolonged life when there is no further hope for cure; hope for a good quality of life when the possibility of prolonging life becomes limited; a lack of hope for some when treatments are no longer effective in curbing illness progression; and for others hope as enjoying the present moment and preparing for the end of life. CONCLUSION: Approaches aimed at sustaining hope need to reflect that patients' reactions might fluctuate between despair and a form of acceptance that leads to a certain serenity. Clinicians need to maintain some degree of hope while remaining as realistic as possible. The findings also raise questions about how hope influences patients' perceptions and acceptance of their treatments.

Subgroup Analyses from a Phase 3, Open-Label, Randomized Study of Eribulin Mesylate Versus Capecitabine in Pretreated Patients with Advanced or Metastatic Breast Cancer.

PURPOSE AND METHODS: Our secondary analyses compared survival with eribulin versus capecitabine in various patient subgroups from a phase 3, open-label, randomized study. Eligible women aged ≥18 years with advanced/metastatic breast cancer and ≤3 prior chemotherapies (≤2 for advanced/metastatic disease), including an anthracycline and taxane, were randomized 1:1 to intravenous eribulin mesylate 1.4 mg/m(2) on days 1 and 8 or twice-daily oral capecitabine 1250 mg/m(2) on days 1-14 (21-day cycles). RESULTS: In the intent-to-treat population (eribulin 554 and capecitabine 548), overall survival appeared longer with eribulin than capecitabine in various subgroups, including patients with human epidermal growth factor receptor 2-negative (15.9 versus 13.5 months, respectively), estrogen receptor-negative (14.4 versus 10.5 months, respectively), and triple-negative (14.4 versus 9.4 months, respectively) disease. Progression-free survival was similar between the treatment arms. CONCLUSIONS: Patients with advanced/metastatic breast cancer and human epidermal growth factor receptor 2-, estrogen receptor-, or triple-negative disease may gain particular benefit from eribulin as first-, second-, and third-line chemotherapies. TRIAL REGISTRATION PRIMARY STUDY: This study reports the subgroup analyses of eribulin versus capecitabine from a phase 3, open-label, randomized study (www.clinicaltrials.gov; ClinicalTrials.gov identifier: NCT00337103).

Use of Intermediate Endpoints in the Economic Evaluation of New Treatments for Advanced Cancer and Methods Adopted When Suitable Overall Survival Data are Not Available.

OBJECTIVES: This study assessed the use of intermediate endpoints in the economic evaluation of new treatments for advanced cancer and the methodological approaches adopted when overall survival (OS) data are unavailable or of limited use. METHODS: A systematic literature review was conducted to identify economic evaluations of treatments for advanced cancer published between 2003 and 2013. Cost-effectiveness and cost-utility analyses expressed in cost per life-year gained and cost per quality-adjusted life-year using an intermediate endpoint as an outcome measure were eligible. Characteristics of selected studies were extracted and comprised population, treatment of interest, comparator, line of treatment, study perspective, and time horizon. Use of intermediate endpoints and methods adopted when OS data were lacking were analyzed. RESULTS: In total, 7219 studies were identified and 100 fulfilled the eligibility criteria. Intermediate endpoints mostly used were progression-free survival and time to progression, accounting for 92 % of included studies. OS data were unavailable for analysis in nearly 25 % of economic evaluations. In the absence of OS data, studies most commonly assumed an equal risk of death for all treatment groups. Other methods included use of indirect comparison based on numerous assumptions, use of a proxy for OS, consultation with clinical experts, and use of published external information from different treatment settings. CONCLUSION: Intermediate endpoints are widely used in the economic evaluation of new treatments for advanced cancer in order to estimate OS. Currently, different methods are used in the absence of suitable OS data and the choice of an appropriate method depends on many factors including the data availability.

Health-related quality of life in patients with locally advanced or metastatic breast cancer treated with eribulin mesylate or capecitabine in an open-label randomized phase 3 trial.

The clinical benefit of eribulin versus capecitabine was evaluated using health-related quality of life (HRQoL) data from a phase 3 randomized trial in patients with pretreated advanced/metastatic breast cancer (ClinicalTrials.gov identifier: NCT00337103). The study population has been described previously (Kaufman et al. in J Clin Oncol 33:594-601, 2015). Eligible patients received eribulin (1.4 mg/m(2) intravenously on days 1 and 8) or capecitabine (1.25 g/m(2) orally twice daily on days 1-14) per 21-day cycles. HRQoL was assessed using the European Organisation for Research and Treatment of Cancer (EORTC) Quality-of-life Questionnaire-Core 30 questions (QLQ-C30) and breast module-23 questions (QLQ-BR23), administered at baseline through 24 months, until disease progression or other antitumor treatment initiation. Minimally important difference (MID) and time to symptom worsening (TSW) were investigated. 1062 (96.4 %) Patients completed the EORTC questionnaire at baseline; overall, compliance was ≥80 %. Patients receiving capecitabine versus eribulin had significantly worse symptoms (higher scores) for nausea/vomiting (MID 8; P < 0.05) and diarrhea (MID 7; P < 0.05). Treatment with eribulin versus capecitabine, led to worse systemic therapy side-effects (dry mouth, different tastes, irritated eyes, feeling ill, hot flushes, headaches, and hair loss; MID 10; P < 0.01). Clinically meaningful worsening was observed for future perspective (MID 10; P < 0.05) with capecitabine and for systemic therapy side-effects scale (MID 10; P < 0.01) with eribulin. Patients receiving capecitabine experienced more-rapid deterioration in body image (by 2.9 months) and future perspective (by 1.4 months; P < 0.05) compared with those on eribulin; the opposite was observed for systemic side-effects where patients receiving eribulin experienced more-rapid deterioration than those receiving capecitabine (by 2 months; P < 0.05). Eribulin and capecitabine were found to have similar impact on patient functioning with no overall difference in HRQoL. Patients receiving eribulin reported worse systemic side-effects of chemotherapy but reduced gastrointestinal toxicity compared with capecitabine.

Phase III open-label randomized study of eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer previously treated with an anthracycline and a taxane.

PURPOSE: This phase III randomized trial (ClinicalTrials.gov identifier: NCT00337103) compared eribulin with capecitabine in patients with locally advanced or metastatic breast cancer (MBC). PATIENTS AND METHODS: Women with MBC who had received prior anthracycline- and taxane-based therapy were randomly assigned to receive eribulin or capecitabine as their first-, second-, or third-line chemotherapy for advanced/metastatic disease. Stratification factors were human epidermal growth factor receptor-2 (HER2) status and geographic region. Coprimary end points were overall survival (OS) and progression-free survival (PFS). RESULTS: Median OS times for eribulin (n = 554) and capecitabine (n = 548) were 15.9 and 14.5 months, respectively (hazard ratio [HR], 0.88; 95% CI, 0.77 to 1.00; P = .056). Median PFS times for eribulin and capecitabine were 4.1 and 4.2 months, respectively (HR, 1.08; 95% CI, 0.93 to 1.25; P = .30). Objective response rates were 11.0% for eribulin and 11.5% for capecitabine. Global health status and overall quality-of-life scores over time were similar in the treatment arms. Both treatments had manageable safety profiles consistent with their known adverse effects; most adverse events were grade 1 or 2. CONCLUSION: In this phase III study, eribulin was not shown to be superior to capecitabine with regard to OS or PFS.

"New" metastases are associated with a poorer prognosis than growth of pre-existing metastases in patients with metastatic breast cancer treated with chemotherapy.

INTRODUCTION: Progression-free survival (PFS) and overall survival (OS) endpoints often only weakly correlate. This analysis investigates how different progression events impact on OS, using data from two phase 3 studies with eribulin in women with advanced/metastatic breast cancer (MBC). METHODS: In Study 301, 1102 women with ≤2 prior chemotherapies for advanced/MBC were randomized to eribulin mesylate (1.4 mg/m(2) on days 1 and 8 every 21 days) or capecitabine (1.25 g/m(2) twice daily on days 1-14 every 21 days). Study 305/EMBRACE enrolled 762 patients following two to five prior chemotherapies for advanced/MBC, randomized to eribulin (as above) or treatment of physician's choice. We analyzed OS and PFS post hoc for patients whose disease progressed due to development of "new" metastases, growth of pre-existing lesions, and patients with no reported disease progression. RESULTS: In both clinical studies, development of new metastases was associated with an increased risk of death (p < 0.0001). The time to development of new metastasis or death was significantly longer with eribulin than the comparator in Study 305 (p = 0.0017), but not in Study 301 (p = 0.46). Significantly longer OS was observed in the eribulin compared with the comparator arm for the new metastases subgroup in Study 301 (p = 0.008), but not in Study 305 (p = 0.16), compared with other progression subgroups. CONCLUSIONS: Patients with MBC progressing with new metastases have a worse prognosis than those whose disease progresses due to growth of existing lesions or patients with no reported disease progression. These findings have potentially important implications for the interpretation of clinical study data and clinical practice. TRIAL REGISTRATION: ClinicalTrials.gov registration IDs: Study 301: NCT00337103 ; Study 305: NCT00388726 .

Progression-free survival as a potential surrogate for overall survival in metastatic breast cancer.

BACKGROUND: Progression-free survival (PFS) and time to progression (TTP) are frequently used to establish the clinical efficacy of anti-cancer drugs. However, the surrogacy of PFS/TTP for overall survival (OS) remains a matter of uncertainty in metastatic breast cancer (mBC). This study assessed the relationship between PFS/TTP and OS in mBC using a trial-based approach. METHODS: WE CONDUCTED A SYSTEMATIC LITERATURE REVIEW ACCORDING TO THE PICO METHOD: 'Population' consisted of women with mBC; 'Interventions' and 'Comparators' were standard treatments for mBC or best supportive care; 'Outcomes' of interest were median PFS/TTP and OS. We first performed a correlation analysis between median PFS/TTP and OS, and then conducted subgroup analyses to explore possible reasons for heterogeneity. Then, we assessed the relationship between the treatment effect on PFS/TTP and OS. The treatment effect on PFS/TTP and OS was quantified by the absolute difference of median values. We also conducted linear regression analysis to predict the effects of a new anti-cancer drug on OS on the basis of its effects on PFS/TTP. RESULTS: A total of 5,041 studies were identified, and 144 fulfilled the eligibility criteria. There was a statistically significant relationship between median PFS/TTP and OS across included trials (r=0.428; P<0.01). Correlation coefficient for the treatment effect on PFS/TTP and OS was estimated at 0.427 (P<0.01). The obtained linear regression equation was ΔOS =-0.088 (95% confidence interval [CI] -1.347-1.172) + 1.753 (95% CI 1.307-2.198) × ΔPFS (R(2)=0.86). CONCLUSION: Results of this study indicate a significant association between PFS/TTP and OS in mBC, which may justify the use of PFS/TTP in the approval for commercialization and reimbursement of new anti-cancer drugs in this cancer setting.

Ixabepilone-associated peripheral neuropathy: data from across the phase II and III clinical trials.

PURPOSE: Dose-limiting neuropathy is a major adverse event associated with most of the microtubule-stabilizing agent-based chemotherapy regimens. Ixabepilone, a semisynthetic analogue of the natural epothilone B, has activity against a wide range of tumor types. Peripheral neuropathy (PN), associated with ixabepilone treatment, is usually mild to moderate, predominantly sensory and cumulative. Preclinical studies demonstrate that ixabepilone and taxanes produce a similar neurotoxicity profile. METHODS: We searched databases of phase II/III clinical trials involving patients receiving ixabepilone as a monotherapy or in combination with capecitabine for incidences of neuropathy. Potential risk factors for grade 3/4 PN were identified by a Cox regression analysis on a dataset of 1,540 patients with different tumor types across multiple studies. RESULTS: Rates for incidence of ixabepilone-induced severe PN (Common Terminology Criteria for Adverse Events grade 3/4) ranged from 1% in early untreated breast cancer up to 24% in heavily pretreated metastatic breast cancer; grade 4 PN was rare (≤ 1%). Common symptoms included numbness, paresthesias, and sometimes dysesthesias. Cox regression analysis identified only preexisting neuropathy as a risk factor for increased ixabepilone-associated PN. The management of PN has been primarily through dose adjustments (dose delays and/or dose reduction). Patients had resolution of their neuropathy within a median time of 5 to 6 weeks. CONCLUSIONS: PN is a dose-limiting toxicity associated with ixabepilone treatment, is reversible in most patients, and can be managed with dose reduction and delays.

Phase II multicenter trial of anthracycline rechallenge with pegylated liposomal doxorubicin plus cyclophosphamide for first-line therapy of metastatic breast cancer previously treated with adjuvant anthracyclines.

PURPOSE: Anthracyclines are a component of breast cancer chemotherapy regimens in both adjuvant and metastatic settings. Anthracycline rechallenge for metastatic disease, for those previously exposed to adjuvant anthracyclines, may not be considered because of concerns about efficacy, tolerability, and cumulative cardiotoxicity. PATIENTS AND METHODS: This prospective, multicenter, single-arm, phase II trial examined the efficacy and safety of pegylated liposomal doxorubicin (PLD) 35 mg/m(2) plus cyclophosphamide 600 mg/m(2) as first-line therapy, delivered every 3 weeks, in 70 patients who developed metastatic disease more than 12 months after completion of an adjuvant anthracycline-containing regimen. Seven patients discontinued treatment early and were excluded from the efficacy analysis. RESULTS: After a median of six cycles, the objective response rate was 38%. An additional 33% of patients achieved stable disease lasting more than 6 months, for an overall clinical benefit rate of 71%. The estimated median time to progression was 12.2 months. Median overall survival time was 16.5 months. Clinical response was equally robust in patients with and without prior taxane exposure. Treatment was well tolerated. The most common grade 3 to 4 toxicities were palmar-plantar erythrodysesthesia (PPE; 10%), dyspnea (9%), and neutropenia (9%). One (1.4%) of 70 patients discontinued treatment as a result of PPE. One patient (1.4%) experienced an infusion reaction requiring discontinuation. No symptomatic cardiac events were observed. CONCLUSION: PLD plus cyclophosphamide is effective and well tolerated in patients with metastatic breast cancer who have received prior adjuvant anthracycline-containing chemotherapy. The majority of patients experienced a clinical benefit without any significant impact on cardiac function.

Phase II clinical trial of ixabepilone (BMS-247550), an epothilone B analog, as first-line therapy in patients with metastatic breast cancer previously treated with anthracycline chemotherapy.

PURPOSE: There is a need for new agents to treat metastatic breast cancer (MBC) in patients for whom anthracycline therapy has failed or is contraindicated. This study was conducted to assess the efficacy and safety of the novel antineoplastic, the epothilone B analog ixabepilone, in patients with MBC previously treated with an adjuvant anthracycline. PATIENTS AND METHODS: Patients were age >or= 18 years and had received a prior anthracycline-based regimen as adjuvant treatment. Ixabepilone as first-line metastatic chemotherapy was administered as a 40 mg/m(2) intravenous infusion during 3 hours every 3 weeks. The primary efficacy end point was objective response rate (ORR). Secondary efficacy end points included duration of response, time to response, time to progression, and survival. RESULTS: All 65 patients were assessable for response. Their median age was 52 years (range, 33 to 80 years). ORR was 41.5% (95% CI, 29.4% to 54.4%), median duration of response was 8.2 months (95% CI, 5.7 to 10.2 months), and median time to response was 6 weeks (range, 5 to 17 weeks). Median survival was 22.0 months (95% CI, 15.6 to 27.0 months). Treatment-related adverse events were manageable and mostly grades 1/2: the most common of these (other than alopecia) was mild to moderate neuropathy, which was primarily sensory and mostly reversible in nature. CONCLUSION: Ixabepilone is efficacious and has a predictable and manageable safety profile in women with MBC previously treated with an adjuvant anthracycline.

Primum non nocere: could the health care system contribute to suffering? In-depth study from the perspective of terminally ill cancer patients.

OBJECTIVE: To explore terminally ill patients' perceptions of their own suffering in order to describe, from these patients' perspective, some elements of health care providers' response to suffering. DESIGN: Qualitative study using content analysis methods suited to a grounded theory approach. SETTING: Teaching and nonteaching hospital oncology clinics, palliative care services (both ambulatory and in-unit), and family practices. PARTICIPANTS: Twenty-six patients diagnosed with terminal cancer. METHODS: Interviews were audiotaped and transcribed verbatim. Data from each interview were coded and categorized to identify and define themes. Themes were discussed and refined until those rating them agreed on them. Data were collected until saturation of emerging issues was reached. MAIN FINDINGS: In our health care system, patients are caught in a pervasive pattern of suffering avoidance, which in turn contributes to increased suffering. Health care services are perceived as a battlefield where physicians and patients are engaged in a losing struggle to ward off illness and death. Both physicians and patients engage in avoiding skepticism and muffling distress. The unavoidable avowal of powerlessness in the face of terminal disease is perceived as capitulation and therapeutic abandonment. Budgetary restraints and understaffing, along with a pervasive culture that implicitly denies death, produce an environment conducive to the avoidance of suffering. To counter this, health care practices that foster increased overlap and continuity between the spheres of oncology, palliative care, and family medicine seem worth developing. CONCLUSION: The suffering of gravely ill patients might be hard to alleviate in the context of modern health care organizations. In some cases, health care delivery directly contributes to increased suffering. Providing support while also helping patients and their families to face upcoming harsh realities is a delicate balancing act that needs to be further explored.

Chemotherapy-induced emesis: quality of life and economic impact in the context of current practice in Canada.

In this study, we estimated the proportion of patients who experience chemotherapy-induced nausea and vomiting (CINV) in current practice and evaluated the impact of CINV on quality of life and cost in Canada. Patients receiving highly emetogenic chemotherapy were recruited from 4 Canadian oncology centers. Patients used diaries to record information on their activities, incidence of nausea and vomiting, and health resources consumed each day for 5 days following chemotherapy. They also completed the Functional Living Index-Emesis (FLIE) questionnaire and a health utility instrument before chemotherapy and 5 days later. Of the 323 patients recruited, 266 (82%) completed their diary. On day 1, 26% of patients reported nausea or vomiting (acute emesis). From day 2 to day 5 after chemotherapy, 44% reported nausea or vomiting (delayed emesis). Patients who experienced nausea or vomiting during the study period had a decrease in FLIE score of 22% and a decrease in health utility of 15%. Patients with nausea or vomiting reported an average of 19 hours per cycle during which they were unable to perform their normal activities. Also, friends or relatives spent an average of 10 hours helping these patients. Incremental medical costs per patient experiencing CINV were $61 Canadian. Including productivity losses, total incremental costs were $592 Canadian per patient. Despite use of antiemetics, CINV remains problematic, impacting the quality of life of patients with cancer and increasing costs.

Recurrence of a non-seminomatous germ cell tumor in the seminal vesicle 20 years after initial diagnosis and treatment.

We present a case of a pathologic stage 1, right sided, non-seminomatous germ cell tumor recurrence in the left seminal vesicle, 20 years after initial diagnosis and treatment. The patient was treated with three salvage cycles of bleomycin, etoposide, and cisplatinum. At 24 months of follow-up after completion of chemotherapy, digital rectal and TRUS examinations revealed complete resolution of the lesion. We believe that this tumor is a late metastasis to the contralateral seminal vesicle.

The nature of suffering and its relief in the terminally ill: a qualitative study.

The essential mandate of medicine is the relief of suffering. However, the quest for an integrated model towards a conceptualization of suffering is still ongoing and empirical studies are few. Qualitative inquiry using 31 in-depth interviews and content analysis was carried out between 1999 and 2001 in 26 patients diagnosed with terminal cancer. The suffering experience was described through a multiplicity of heterogenous elements from the physical, psychological, and social spheres. Systematic synthesis of interview material yielded three apparently irreducible core dimensions. Respondents defined their suffering in terms of 1) being subjected to violence, 2) being deprived and/or overwhelmed, and 3) living in apprehension. Cassell wrote, in 1991, that to know the suffering of others demands an exhaustive understanding of what makes them the individuals they are (1). Our model can be of use in structuring and eliciting this necessary information. Understanding how a particular patient feels harmed, deprived or overburdened, and overtaken by fear, provides a lever for action tailored to the specifics of that person's experience.

Activity and safety of the antiestrogen EM-800, the orally active precursor of acolbifene, in tamoxifen-resistant breast cancer.

PURPOSE: To determine the efficacy and safety of EM-800 (SCH-57050), the precursor of acolbifene, a new, highly potent, orally active, pure antiestrogen in the mammary gland and endometrium, for the treatment of tamoxifen-resistant breast cancer. PATIENTS AND METHODS: Forty-three post menopausal/ovariectomized women with breast cancer who had received tamoxifen, either for metastatic disease or as adjuvant to surgery for > or = 1 year, and had relapsed were treated in a prospective, multicenter, phase II study with EM-800 (20 mg/d [n = 21] or 40 mg/d [n = 22] orally). Results Thirty-seven patients had estrogen receptor (ER)-positive tumors (>10 fmol/mg; mean, 146 fmol/mg cytosolic protein), three patients had ER-negative/progesterone receptor-positive tumors, and three patients had undetermined ER status. The objective response rate to EM-800 was 12%, with one complete response and four partial responses. Ten patients (23%) had stable disease for > or = 3 months, and 7 patients (16%) had stable disease for > or = 6 months. With a median follow-up of 29 months, median duration of response was 8 months (range, 7 to 71+ months). Treatment with EM-800 was well tolerated. No significant adverse events related to the study drug were observed clinically or biochemically. CONCLUSION: EM-800 produced responses in a significant proportion of patients with tamoxifen-resistant breast cancer, thus showing that this highly potent, selective estrogen receptor modulator, which lacks estrogenic activity in the mammary gland and endometrium, has incomplete cross-resistance with tamoxifen, thus suggesting additional benefits in the treatment of breast cancer.