Neratinib as adjuvant therapy in patients with HER2 positive breast cancer: expert opinion.

Neratinib is a tyrosine kinase receptor inhibitor used in the extended adjuvant therapy of early-stage breast cancer. After adjuvant trastuzumab therapy, neratinib reduces the risk of recurrence and, if taken within 1 year from trastuzumab, significantly improves the invasive disease-free survival of patients with early-stage human epidermal growth factor receptor-2 positive (HER2+) breast cancer with no increased risk of long-term toxicity. Diarrhea, the most common adverse event associated with neratinib use, deters some clinicians from prescribing this drug. However, neratinib-related toxicity is predictable, short-lived, mostly limited to the first month of treatment and can be managed with dose-escalation and prophylactic strategies. Thus, close surveillance and prompt management, relying on supportive care and administration schedule modification, allows discontinuation of treatment to be avoided.

Extended adjuvant endocrine treatment for premenopausal women: A Delphi approach to guide clinical practice.

The use of an aromatase inhibitor (AI) in combination with ovarian function suppression (OFS) has become the mainstay of adjuvant endocrine therapy in high-risk premenopausal patients with hormone receptor-positive breast cancer. Although five years of such therapy effectively reduces recurrence rates, a substantial risk of late recurrence remains in this setting. Multiple trials have shown that extending AI treatment beyond five years could offer further protection. However, as these studies comprised only postmenopausal patients, no direct evidence currently exists to inform about the potential benefits and/or side effects of extended AI + OFS therapies in premenopausal women. Given these grey areas, we conducted a Delphi survey to report on the opinion of experts in breast cancer treatment and summarize a consensus on the discussed topics. A total of 44 items were identified, all centred around two main themes: 1) defining reliable prognostic factors to pinpoint premenopausal patients eligible for endocrine therapy extension; 2) designing how such therapy should optimally be administered in terms of treatment combinations and duration based on patients' menopausal status. Each item was separately discussed and anonymously voted by 12 experts representing oncological institutes spread across Italy. The consensus threshold was reached in 36 out of 44 items (82%). Herein, we discuss the levels of agreement/disagreement achieved by each item in relation to the current body of literature. In the absence of randomized trials to guide the tailoring of extended AI treatment in premenopausal women, conclusions from our study provide a framework to assist routine clinical practice.

Tumour Burden Reporting in Phase III Clinical Trials of Metastatic Lung, Breast, and Colorectal Cancers: A Systematic Review.

BACKGROUND: Randomised phase III clinical trials represent a methodological milestone to select effective drugs against metastatic cancers. In this context, and particularly in the efficacy assessment of biologic drugs, the initial metastatic tumour burden is a strong prognostic factor. METHODS: A systematic literature review of randomised, phase III, first-line, clinical trials in metastatic breast, colorectal, and lung cancers, published from 2016 to 2021, was performed. Three groups of variables were collected: identity-, method- (including tumour burden assessment) and outcome-related. RESULTS: Seventy trials were selected. A large portion of studies (41.4%) focused on the effects of biologic agents (signal inhibitors and immuno-therapies). A definition of low-burden disease based predominantly on the number of involved organs was reported in 28.6% of studies. No explicit reference to oligo-metastatic disease was found either in inclusion/exclusion criteria or in final descriptive data analyses. Disease extent, heterogeneously defined, was a stratification factor for randomisation in only 25.7% of studies. In two studies, a significant imbalance between arms in patients with low-burden disease was revealed. CONCLUSIONS: Attention to initial tumour burden in designing future clinical trials (including the harmonisation of definitions and the reporting of eventual oligo-metastatic disease, complete estimates of tumour volume, and its consideration as a stratification factor) should be increased.

Uptake of Trastuzumab Biosimilars for the Treatment of HER2-Positive Breast Cancer: A Real-World Experience from a Cancer Center.

BACKGROUND: The introduction of trastuzumab biosimilars in clinical practice plays an important role in promoting the sustainability of healthcare systems. By contrast, the switching process can be challenging to the clinics. This survey describes the switching process at a National Cancer Institute over a period of 2 years. METHODS: Data regarding all trastuzumab-based regimens for breast cancer (BC) from 1 January 2019 and 31 December 2020 were extracted from both adverse drug reactions (ADRs) reporting systems and electronic systems involved in inventory management, prescribing, dispensing, and administration. Both patients under monotherapy and combination treatment regimens were included. There were no exclusion criteria. RESULTS AND CONCLUSIONS: Overall 354 patients received at least one trastuzumab-based regimen for a total of 493 lines of treatment and 5769 administrations. Biosimilar were used in 34.3% of trastuzumab-based treatments. No differences between biosimilars and reference drug have been observed in terms of ADRs. The effective cost-saving of the first 2 years is greater than EUR 800,000 and it is estimated to increase over time.

Cancer Treatment-Induced Bone Loss (CTIBL): State of the Art and Proper Management in Breast Cancer Patients on Endocrine Therapy.

OPINION STATEMENT: About 70-80% of early breast cancer (BC) patients receive adjuvant endocrine therapy (ET) for at least 5 years. ET includes in the majority of cases the use of aromatase inhibitors, as upfront or switch strategy, that lead to impaired bone health. Given the high incidence and also the high prevalence of BC, cancer treatment-induced bone loss (CTIBL) represents the most common long-term adverse event experimented by patients with hormone receptor positive tumours. CTIBL is responsible for osteoporosis occurrence and, as a consequence, fragility fractures that may negatively affect quality of life and survival expectancy. As recommended by main international guidelines, BC women on aromatase inhibitors should be carefully assessed for their fracture risk at baseline and periodically reassessed during adjuvant ET in order to early detect significant worsening in terms of bone health. Antiresorptive agents, together with adequate intake of calcium and vitamin D, should be administered in BC patients during all course of ET, especially in those at high risk of osteoporotic fractures, as calculated by tools available for clinicians. Bisphosphonates, such as zoledronate or pamidronate, and anti-RANKL antibody, denosumab, are the two classes of antiresorptive drugs used in clinical practice with similar efficacy in preventing bone loss induced by aromatase inhibitor therapy. The choice between them, in the absence of direct comparison, should be based on patients' preference and compliance; the different safety profile is mainly related to the route of administration, although both types of drugs are manageable with due care, since most of the adverse events are predictable and preventable. Despite advances in management of CTIBL, several issues such as the optimal time of starting antiresorptive agents and the duration of treatment remain unanswered. Future clinical trials as well as increased awareness of bone health are needed to improve prevention, assessment and treatment of CTIBL in these long-term survivor patients.

Folinic acid in colorectal cancer: esquire or fellow knight? Real-world results from a mono institutional, retrospective study.

The stock of therapeutic weapons available in metastatic colorectal cancer (mCRC) has been progressively grown over the years, with improving both survival and patients' clinical outcome: notwithstanding advances in the knowledge of mCRC biology, as well as advances in treatment, fluoropyrimidine antimetabolite drugs have been for 30 years the mainstay of chemotherapy protocols for this malignancy. 5-Fluorouracil (5FU) seems to act differently depending on administration method: elastomer-mediated continuous infusion better inhibits Thymidylate Synthase (TS), an enzyme playing a pivotal role in DNA synthetic pathway. TS overexpression is an acknowledged poor prognosis predicting factor. The simultaneous combination of 5FU and folinate salt synergistically strengthens fluorouracil cytotoxic effect. In our experience, levofolinate and 5FU together in continuous infusion prolong progression free survival of patients suffering from mCRC, moreover decreasing death risk and showing a clear clinical benefit for patients, irrespective of RAS mutational status, primitive tumor side and metastases surgery.

Genomic Aberrations and Late Recurrence in Postmenopausal Women with Hormone Receptor-positive Early Breast Cancer: Results from the SOLE Trial.

PURPOSE: Women with hormone receptor-positive early breast cancers have a persistent risk of relapse and biomarkers for late recurrence are needed. We sought to identify tumor genomic aberrations associated with increased late-recurrence risk. EXPERIMENTAL DESIGN: In a secondary analysis of Study of Letrozole Extension trial, a case-cohort-like sampling selected 598 primary breast cancers for targeted next-generation sequencing analysis of gene mutations and copy-number gains (CNGs). Correlations of genomic aberrations with clinicopathologic factors and breast and distant recurrence-free intervals (BCFIs and DRFIs) were analyzed using weighted Cox models. RESULTS: Analysis of mutations and CNGs was successfully performed for 403 and 350 samples, including 148 and 134 patients with breast cancer recurrences (median follow-up time, 5.2 years), respectively. The most frequent alterations were PIK3CA mutations (42%) and CNGs of CCND1 (15%), ERBB2 (10%), FGFR1 (8%), and MYC (8%). PIK3CA mutations and MYC CNGs were associated with lower (P = 0.03) and higher (P = 0.004) tumor grade, respectively; a higher Ki-67 was seen in tumor with CCND1, ERBB2, and MYC CNGs (P = 0.01, P < 0.001, and P = 0.03, respectively). FGFR1 CNG was associated with an increased risk of late events in univariate analyses [17/29 patients; BCFI: HR, 3.2; 95% confidence interval (CI), 1.48-6.92; P = 0.003 and DRFI: HR, 3.5; 95% CI, 1.61-7.75; P = 0.002) and in multivariable models adjusted for clinicopathologic factors. CONCLUSIONS: Postmenopausal women with hormone receptor-positive early breast cancer harboring FGFR1 CNG had an increased risk of late recurrence despite extended therapy. FGFR1 CNG may represent a useful prognostic biomarker for late recurrence and a therapeutic target.

Targeting Autophagy in Breast Cancer.

Breast cancer is a heterogeneous disease consisting of different biological subtypes, with differences in terms of incidence, response to diverse treatments, risk of disease progression, and sites of metastases. In the last years, several molecular targets have emerged and new drugs, targeting PI3K/Akt/mTOR and cyclinD/CDK/pRb pathways and tumor microenvironment have been integrated into clinical practice. However, it is clear now that breast cancer is able to develop resistance to these drugs and the identification of the underlying molecular mechanisms is paramount to drive further drug development. Autophagy is a highly conserved homeostatic process that can be activated in response to antineoplastic agents as a cytoprotective mechanism. Inhibition of autophagy could enhance tumor cell death by diverse anti-cancer therapies, representing an attractive approach to control mechanisms of drug resistance. In this manuscript, we present a review of autophagy focusing on its interplay with targeted drugs used for breast cancer treatment.

Impact of COVID-19 outbreak on cancer immunotherapy in Italy: a survey of young oncologists.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has overwhelmed the health systems worldwide. Data regarding the impact of COVID-19 on cancer patients (CPs) undergoing or candidate for immune checkpoint inhibitors (ICIs) are lacking. We depicted the practice and adaptations in the management of patients with solid tumors eligible or receiving ICIs during the COVID-19 pandemic, with a special focus on Campania region. METHODS: This survey (25 questions), promoted by the young section of SCITO (Società Campana di ImmunoTerapia Oncologica) Group, was circulated among Italian young oncologists practicing in regions variously affected by the pandemic: high (group 1), medium (group 2) and low (group 3) prevalence of SARS-CoV-2-positive patients. For Campania region, the physician responders were split into those working in cancer centers (CC), university hospitals (UH) and general hospitals (GH). Percentages of agreement, among High (H) versus Medium (M) and versus Low (L) group for Italy and among CC, UH and GH for Campania region, were compared by using Fisher's exact tests for dichotomous answers and χ2 test for trends relative to the questions with 3 or more options. RESULTS: This is the first Italian study to investigate the COVID-19 impact on cancer immunotherapy, unique in its type and very clear in the results. The COVID-19 pandemic seemed not to affect the standard practice in the prescription and delivery of ICIs in Italy. Telemedicine was widely used. There was high consensus to interrupt immunotherapy in SARS-CoV-2-positive patients and to adopt ICIs with longer schedule interval. The majority of the responders tended not to delay the start of ICIs; there were no changes in supportive treatments, but some of the physicians opted for delaying surgeries (if part of patients' planned treatment approach). The results from responders in Campania did not differ significantly from the national ones. CONCLUSION: Our study highlights the efforts of Italian oncologists to maintain high standards of care for CPs treated with ICIs, regardless the regional prevalence of COVID-19, suggesting the adoption of similar solutions. Research on patients treated with ICIs and experiencing COVID-19 will clarify the safety profile to continue the treatments, thus informing on the most appropriate clinical conducts.

Progression-Free Survival and Overall Survival of CDK 4/6 Inhibitors Plus Endocrine Therapy in Metastatic Breast Cancer: A Systematic Review and Meta-Analysis.

The introduction of CDK4/6 inhibitors in combination with endocrine therapy (ET) represents the most relevant advance in the management of hormone receptor (HR) positive, HER2-negative metastatic breast cancer over the last few years. This meta-analysis of randomized controlled trials (RCTs) is aimed to better characterize the efficacy of CDK4/6 inhibitors in some relevant subgroups and to test heterogeneity between different compounds with a particular focus on their ability to improve overall survival (OS). Pooled estimates of hazard ratios (HRs) were computed for progression-free survival (PFS), OS, and objective response rate (ORR) analysis in predefined subgroups to better understand treatment effect concerning specific patients' characteristics. To estimate the absolute benefit in terms of PFS, pooled survival curves were generated by pooling the data of all trials. A total of eight RCTs were included. Adding a CDK4/6 inhibitor to ET is beneficial in terms of PFS, irrespective of the presence or not of visceral metastases, the number of metastatic sites, and the length of the treatment-free interval (TFI). The addition of CDK4/6 inhibitors produces a significant OS improvement, both in aromatase inhibitor (AI)-sensitive (HR 0.75, 95% CI) and AI-resistant patients (HR 0.77, 95% CI [0.67-0.89]). Pooled data from each single drug show that palbociclib remains the only class member not showing a statistically significant HR for OS (HR 0.83, 95% CI [0.68-1.02]).

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.

Systemic treatment of malignant gastrointestinal neuroectodermal tumour after childhood neuroblastoma: chemotherapy in malignant gastrointestinal neuroectodermal tumour.

Malignant gastrointestinal neuroectodermal tumour is an extremely rare neoplasm that arises in the wall of the small bowel, stomach or large bowel in young-aged and middle-aged adults. Histologically, it is generally characterized by monomorphic cells with clear cytoplasma, S-100 protein expression, and EWSR1 gene translocation. To the best of our knowledge, we describe for the first time, the case of a young woman with a diagnosis of metastatic gastrointestinal neuroectodermal tumour arising from ileum, who had a childhood adrenal neuroblastoma with liver, bone and lymph nodes metastasis, treated with four cycles of chemotherapy with the schedule CADO-CVP (CADO: cyclophosphamide 300 mg/m/day on days 1-5, vincristine 1,5 mg/m/day on days 1 and 5, and doxorubicin 60 mg/m/day on day 5; CVP: cisplatin 40 mg/m/day on days 1-5 and etoposide 100 mg/m/day on days 1-5) followed by right adrenal, kidney, lymph nodes and liver lesion resection, conditioning chemotherapy (melphalan-carmustine-teniposide), stem cells autologous transplantation and consecutively radiotherapy on the spine (T9 to L3) for a total of 30 Gy. For the second diagnosis of gastrointestinal neuroectodermal tumour with liver metastasis, she underwent ileal tumour resection and platinum-anthracycline based chemotherapy with initial shrinkage of liver metastasis. Unfortunately, despite the initial response and the following delivered therapies, she died for rapid progressive disease. Taking into account the late effects of past therapeutic modalities, a long-term surveillance of young child treated for neuroblastoma, is required to appreciate their overall risks of second malignancies.

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.

Extended adjuvant intermittent letrozole versus continuous letrozole in postmenopausal women with breast cancer (SOLE): a multicentre, open-label, randomised, phase 3 trial.

BACKGROUND: In animal models of breast cancer, resistance to continuous use of letrozole can be reversed by withdrawal and reintroduction of letrozole. We therefore hypothesised that extended intermittent use of adjuvant letrozole would improve breast cancer outcome compared with continuous use of letrozole in postmenopausal women. METHODS: We did the multicentre, open-label, randomised, parallel, phase 3 SOLE trial in 240 centres (academic, primary, secondary, and tertiary care centres) in 22 countries. We enrolled postmenopausal women of any age with hormone receptor-positive, lymph node-positive, and operable breast cancer for which they had undergone local treatment (surgery with or without radiotherapy) and had completed 4-6 years of adjuvant endocrine therapy. They had to be clinically free of breast cancer at enrolment and without evidence of recurrent disease at any time before randomisation. We randomly assigned women (1:1) to treatment groups of either continuous use of letrozole (2·5 mg/day orally for 5 years) or intermittent use of letrozole (2·5 mg/day orally for 9 months followed by a 3-month break in years 1-4 and then 2·5 mg/day during all 12 months of year 5). Randomisation was done by principal investigators or designee at respective centres through the internet-based system of the International Breast Cancer Study Group, was stratified by type of previous endocrine therapy (aromatase inhibitors only vs selective oestrogen receptor modulators only vs both therapies), and used permuted block sizes of four and institutional balancing. No one was masked to treatment assignment. The primary endpoint was disease-free survival, analysed by the intention-to-treat principle using a stratified log-rank test. All patients in the intention-to-treat population who initiated protocol treatment during their period of trial participation were included in the safety analyses. This study is registered with ClinicalTrials.gov, number NCT00553410, and EudraCT, number 2007-001370-88; and long-term follow-up of patients is ongoing. FINDINGS: Between Dec 5, 2007, and Oct 8, 2012, 4884 women were enrolled and randomised after exclusion of patients at a non-adherent centre, found to have inadequate documentation of informed consent, immediately withdrew consent, or randomly assigned to intervention groups in error. 4851 women comprised the intention-to-treat population that compared extended intermittent letrozole use (n=2425) with continuous letrozole use (n=2426). After a median follow-up of 60 months (IQR 53-72), disease-free survival was 85·8% (95% CI 84·2-87·2) in the intermittent letrozole group compared with 87·5% (86·0-88·8) in the continuous letrozole group (hazard ratio 1·08, 95% CI 0·93-1·26; p=0·31). Adverse events were reported as expected and were similar between the two groups. The most common grade 3-5 adverse events were hypertension (584 [24%] of 2417 in the intermittent letrozole group vs 517 [21%] of 2411 in the continuous letrozole group) and arthralgia (136 [6%] vs 151 [6%]). 54 patients (24 [1%] in the intermittent letrozole group and 30 [1%] in the continuous letrozole group) had grade 3-5 CNS cerebrovascular ischaemia, 16 (nine [<1%] vs seven [<1%]) had grade 3-5 CNS haemorrhage, and 40 (19 [1%] vs 21 [1%]) had grade 3-5 cardiac ischaemia. In total, 23 (<1%) of 4851 patients died while on trial treatment (13 [<1%] of 2417 patients in the intermittent letrozole group vs ten [<1%] of 2411 in the continuous letrozole group). INTERPRETATION: In postmenopausal women with hormone receptor-positive breast cancer, extended use of intermittent letrozole did not improve disease-free survival compared with continuous use of letrozole. An alternative schedule of extended adjuvant endocrine therapy with letrozole, including intermittent administration, might be feasible and the results of the SOLE trial support the safety of temporary treatment breaks in selected patients who might require them. FUNDING: Novartis and the International Breast Cancer Study Group.

Trastuzumab and Gemcitabine in Pretreated HER2 Overexpressing Metastatic Breast Cancer Patients: Retrospective Analysis of Our Series.

Trastuzumab-based regimes improved clinical outcome in women with overexpressing HER2 metastatic breast cancer, mainly due to the availability of different combination therapies, clinically active and well tolerated. In this study we retrospectively evaluated clinical activity and toxicity of trastuzuamb plus gemcitabine regimen in heavily pretreated HER2 positive metastatic breast cancer patients. Although the observed population was heavily pretreated, the evaluated regimen was notably effective in terms of response rate, time to progression and survival, with very mild toxicity. These data suggest that in over expressing HER2 metastatic breast cancer patients, sequential trastuzumab based chemotherapeutic regimens can achieve good response rate with prolonged TTP in responding patients, even after other target therapy such as lapatinib based combinations.

Target therapy in elderly breast cancer patients.

Substantial progress has been made in the management of breast cancer by targeting HER2 and VEGF pathways. Although the efficacy and safety of target therapy in breast cancer have been established, no specific phase III trial has addressed these issues in the elderly population and the only data available derive from subanalyses or retrospective series. The aim of this review is to summarize the available evidence in this special population and to encourage further well designed studies in elderly breast cancer patients.

Trastuzumab and vinorelbine as highly effective and safe therapy for HER-2-overexpressing metastatic breast cancer. A single institution experience.

AIMS AND BACKGROUND: Trastuzumab-based therapy has improved survival of women with human epidermal growth factor receptor 2 (HER2)-overexpressing metastatic breast cancer. STUDY DESIGN: From September 2002 to July 2006, 45 women with metastatic breast cancer HER2 3+, or 2+ and positive for HER2 gene amplification, were enrolled in the study and received a combination therapy with vinorelbine, 25 mg/m2 weeks 1 and 2, plus trastuzumab, 4 mg/kg loading dose and then 2 mg/kg weekly, in a three weeks cycle. Eligibility criteria included measurable disease and a baseline ejection fraction > or = 50%. Forty-two percent of the patients were not pretreated, whereas 58% had received a previous chemotherapy regimen for metastatic disease, including anthracyclines and/or taxanes (47%), and trastuzumab plus taxol (11%). RESULTS: We observed 14 (31%) complete responses and 21 (47%) partial responses, with an overall response rate of 78%. Stable disease > 6 months was assessed for 5 (11%) patients with a clinical benefit of 89%. Five (11%) patients progressed. With a median follow-up of 11 months, median time to progression was 9 months and median duration of response was 7.6 months for complete remissions and 4 months for partial remissions. Median survival was 29 months. CONCLUSIONS: In spite of a smaller dose intensity of vinorelbine than previously reported, the regimen evaluated was notably effective in terms of response rate, time to progression and survival, with very mild toxicity.

Combined chemoimmunotherapy of metastatic melanoma: a single institution experience.

The addition of cytokines, such as interferon alpha-2b and interleukin-2, to chemotherapy in metastatic melanoma has produced conflicting results in phase II and III trials. We report our experience with a chemoimmunotherapeutic regimen using subcutaneous cytokines. Twenty-eight patients with advanced melanoma (median age, 45 years; male to female ratio, 19 : 9) were treated. Doses were as follows: cisplatin, 20 mg/m intravenously (iv) days 1-4; vinblastine, 1.6 mg/m iv days 1-4; dacarbazine, 800 mg/m iv day 1; interferon alpha-2b, 5 MIU/m subcutaneously (sc) days 1-5; interleukin-2, 9 MIU/m sc days 1-5 and 8-12. Treatment was repeated every 3 weeks for a maximum of six cycles. The response was assessed after two cycles and toxicity at every cycle, according to World Health Organization (WHO) and National Cancer Institute (NCI) criteria, respectively. At a median follow-up of 8 months, only four patients (14%) were still alive. The overall response rate was 33%, with three (11%) complete responses lasting for 17, 14 and >24 months. There were six (22%) partial responses and three stable disease. Amongst the responders, three patients progressed at the level of the central nervous system. The median time to progression and overall survival were 3.5 and 9 months, respectively. The most common grade 3-4 toxicity was neutropenia, reported in 25 of the 28 patients (92%). Only two patients (7%) experienced neutropenic fever. Thrombocytopenia grade 3-4 occurred in seven of the 28 patients (25%), with only one patient needing transfusional support. One toxic death due to neutropenic fever occurred. It can be concluded that the chemoimmunotherapy schedule evaluated is active and may be considered for patients with metastatic melanoma who have a good performance status and a limited disease burden.

Long-term, weekly one-hour infusion of paclitaxel in patients with metastatic breast cancer: a phase II monoinstitutional study.

AIMS AND BACKGROUND: A dose-dense therapy with weekly paclitaxel given as a 1-hr infusion yielded a 53% overall response rate in breast cancer patients resistant to anthracyclines, with a remarkable lack of neutropenia (Seidman, 1998). We performed a monoinstitutional phase II trial in order to confirm these interesting results. PATIENTS AND METHODS: Eligibility criteria included advanced breast cancer and no taxane pretreatment. Paclitaxel was administered weekly at the dose of 90 mg/m2 (60 mg/m2 in patients at high risk of toxicity) by 1-hr i.v. infusion. Fifty-eight patients entered the trial. Median age was 54 years (range, 38-72). Performance status was good (median 1; range, 0-2). Fifty-two patients were pretreated with anthracyclines. RESULTS: A total of 1,004 weekly paclitaxel infusions were administered (median, 19 per patient; range, 4-43). The median delivered dose intensity was 67.4 mg/m2/week (range, 43-86). Twenty-eight of the 58 assessable patients obtained an objective response (48%), 15 had stable disease (26%) and 15 progressed (26%). The overall response rate was 48% (95% confidence interval, 35-61%) with 5 complete responses (8%). In anthracycline-pretreated patients, 23/52 (44%) responses were observed. Median duration of response was 5 months (range, 3-27). Toxicity was acceptable apart from a case of pulmonary embolism in a 70-year-old patient, 1 case of congestive heart failure in an anthracycline-pretreated patient aged 64, and 9 cases of G3 neutropenia. Peripheral neuropathy was observed in 38 patients (64%), usually of a mild grade; alopecia in 45 patients (78%) and onychopathy in 16 (28%), usually of a mild grade apart from 2 cases requiring treatment interruption. Tachycardia and atrial fibrillation occurred in a 55-year-old woman. CONCLUSIONS: Our data seem to confirm the activity and safety of this approach even in a heavily pretreated population of patients. Its combination with other active drugs needs to be further investigated in clinical trials.

Acceptance of external infusion pumps in patients with advanced breast cancer receiving continuous infusion fluorouracil.

BACKGROUND: We investigated the physical and psychological adaptation to a protracted continuous infusion system in a series of patients receiving protracted continuous infusion of 5-fluorouracil for advanced breast cancer. PATIENTS AND METHODS: The protracted continuous infusion of 5-fluorouracil was administered by means of a portable elastomeric pump (Baxter Seven-Day Infusor, 0.5 mL/hr) via an indwelling Groshong catheter. Patients were asked to complete a questionnaire exploring the impact of the continuous infusion system upon various aspects of daily life, the overall level of disturbance, the general judgement on its quality, and their willingness to resume the same kind of treatment in the future. All items were graded on a 4-point scale from 0 = not at all, to 4 = very much. RESULTS: Seventy-one patients were evaluated. All patients received 5-fluorouracil at the dose of 250 mg/m2/day as a protracted continuous infusion alone (n = 14) or in combination with vinorelbine (n = 45) or Taxol (n = 12). The median duration of the protracted continuous infusion before evaluation was 9 months (3-31). The mean level of disturbance to daily activities was 0.86 points. The activities most frequently disturbed by treatment included daily personal care (mean, 1.76 points) and sexual activity (mean, 1.20 points). Twenty-one patients required medical intervention because of problems related to the protracted continuous infusion system. The overall level of disturbance was rated at a mean level of 0.72 points, whereas the overall merits of the protracted continuous infusion system and the willingness of the patient to resume protracted continuous infusion in the future were rated at a mean level of 2.90 and 2.55 points, respectively. CONCLUSIONS: The system for the protracted continuous infusion of 5-fluorouracil was well tolerated by the patients, who were able in most cases to perform their daily activities with little or no disturbance, needing only occasional help, and were willing to resume the same treatment modality if necessary.