Primary systemic therapy in HER2-amplified breast cancer : a clinical review

Primary systemic therapy (PST) in early breast cancer is utilized in locally advanced breast tumors and when breast-conserving surgery is desirable. In addition, the PST setting provides an opportunity to monitor response including histopathological and biomarker examination of the tumor and host tissues before and after systemic therapy. Trastuzumab is a monoclonal antibody targeting the hEGF receptor that is overexpressed in 15–20% of breast tumors. Trastuzumab is effective in prolonging survival when used to treat women with hEGF receptor overexpressed tumors, both in adjuvant and metastatic disease settings. Trastuzumab has also shown promising activity in PST/neoadjuvant studies by achieving high rates of complete pathologic response. This is a review of clinical studies that incorporated trastuzumab in PST and/or neoadjuvant chemotherapy, including the results of recently reported studies using trastuzumab in combination with other novel therapies such as lapatinib or pertuzumab.

Chemotherapy in the elderly

The number of elderly patients with malignancy is growing and is likely to have a major impact on resources, quality of care, health economics and treatment options. Decisions regarding treatment options with chemotherapy are limited by the scarcity of data specifically addressing the issues regarding chemotherapy in the elderly. The problem is further confounded by issues such as co morbidity, poly-pharmacy, cognitive impairments, emotional problems, functional limitations, sensory impairment and a lack of social support. Ageing is associated with specific physiologic changes in functional status, organ function and drug pharmacokinetics. Optimising cancer care and chemotherapy delivery in the elderly requires a better understanding of the specific pharmacokinetic and pharmacodynamic issues and administration of chemotherapy in this age group. Elderly participation in clinical trials and specific research is essential to guide treatment decisions and further research is required to provide evidence-based models to guide treatment decisions. In an Australian setting, the development of a geriatric oncology specific group as a means of facilitating collaboration with geriatricians, development of specific elderly research programs and clinical trials, education and development of treatment guidelines would further improve outcomes of our elderly patients undergoing cancer treatment.

Goblet cell carcinoid tumors (adenocarcinoid) of the appendix

Purpose: Goblet cell appendiceal carcinoids represent rare tumors that exhibit histologic features of both adenocarcinomas and neuroendocrine tumors. We present the long-term results of a series of 15 patients, focusing on clinical manifestations, diagnosis, and management.

Methods: Eight male and seven female patients (median age, 52.8 years) were included. Final diagnosis was confirmed by histology. Patients were evaluated clinically, biochemically, and radiologically every four months. Median follow-up was 30 months.

Results: The majority of patients (7/15) presented with symptoms compatible with acute appendicitis. Right hemicolectomy was performed in all except one, who subsequently developed metastases. Three patients had metastases at previous diagnosis. Plasma chromogranin-A was slightly elevated in two of them, while urinary 5-hydroxy-indol-acetic acid was normal. 111Indium-labeled octreotide scintigraphy was positive only in two of the four patients with metastases. Ki67 index was greater than 20 percent in all of them, while in only one with local tumor. Combination chemotherapy with either cisplatin plus etoposide or with 5-fluorouracil, cisplatin, and streptozotocin was administered to all patients with metastases resulting in temporary stabilization of disease. Twelve patients are alive, while three died of their disease 9, 13, and 14 months after diagnosis.

Conclusions: The diagnostic value of chromogranin-A, urinary 5-hydroxy-indol-acetic acid, and 111Indium-labeled octreotide scintigraphy seems to be limited in these tumors. Ki67 index appears to predict tumor behavior. Right hemicolectomy may reduce the risk of developing metastases. Chemotherapy may have efficacy in metastatic disease, however, more data are required to determine this and the optimal regimen.

Patterns of care in adult medulloblastoma: results of an international online survey

The literature on medulloblastoma in adults is generally limited to case reports and retrospective series, and there is no accepted standard of care. The Cooperative Trials Group for Neuro-Oncology (COGNO) sought to determine the range and consistency of clinicians’ approaches to management as a basis for future trials. We aimed to identify current treatment strategies for adult medulloblastoma through an online survey launched at the 2012 Society of Neuro-Oncology meeting and by email invitation. Clinicians who had treated at least one adult patient with medulloblastoma, primitive neuroectodermal tumor (PNET), or pineoblastoma in the preceding year were asked about their most recent patient and invited to discuss their approach to a typical clinical scenario. Between November 2012 and January 2013, 45 clinicians (11 medical oncologists, 8 radiation oncologists, 5 pediatric oncologists, and 21 others) from Australia (24), United States (3), Europe (4) and other countries (14) completed the survey. Responding clinicians had treated 54 cases in the past 12 months. The most common histological type was medulloblastoma (64 %), then PNET (20 %). Most patients were male (68 %), and had high-risk disease (65 %). Complete surgical resection in 56 and 32 % had molecular testing. Radiotherapy was predominantly cranio-spinal (92 %) and given mostly post-resection (80 %). Combination chemotherapy was more common than single-agent chemotherapy. The choice of chemotherapy varied considerably. There is substantial variation in the treatment of adult medulloblastoma, most pronounced in the choice of chemotherapeutic agents, highlighting the need for further collaborative research to guide evidence-based treatment strategies.

Multicentre phase I/II study of PI-88, a heparanase inhibitor in combination with docetaxel in patients with metastatic castrate-resistant prostate cancer

Background: Docetaxel (Taxotere) improve survival and prostate-specific antigen (PSA) response rates in patients with metastatic castrate-resistant prostate cancer (CRPC). We studied the combination of PI-88, an inhibitor of angiogenesis and heparanase activity, and docetaxel in chemotherapy-naive CRPC.

Patients and methods: We conducted a multicentre open-label phase I/II trial of PI-88 in combination with docetaxel. The primary end point was PSA response. Secondary end points included toxicity, radiologic response and overall survival. Doses of PI-88 were escalated to the maximum tolerated dose; whereas docetaxel was given at a fixed 75 mg/m2 dose every three weeks

Results: Twenty-one patients were enrolled in the dose-escalation component. A further 35 patients were randomly allocated to the study to evaluate the two schedules in phase II trial. The trial was stopped early by the Safety Data Review Board due to a higher-than-expected febrile neutropenia of 27%. In the pooled population, the PSA response (50% reduction) was 70%, median survival was 61 weeks (6–99 weeks) and 1-year survival was 71%.

Conclusions: The regimen of docetaxel and PI-88 is active in CRPC but associated with significant haematologic toxicity. Further evaluation of different scheduling and dosing of PI-88 and docetaxel may be warranted to optimise efficacy with a more manageable safety profile.

Capecitabine and oral cyclophosphamide : a novel oral treatment combination for advanced cancer

Background: This dose escalation study assessed feasibility of a totally oral chemotherapy regimen using cyclophosphamide and capecitabine. The rationale for this combination was based on the observation that preclinical models of cyclophosphamide up-regulated tumor thymidine phosphorylase and increased the activation of capecitabine. Methods: Eligible patients with advanced cancer were treated with oral cyclophosphamide and capecitabine on a 28-day cycle. If no dose limiting toxicities (DLT) were encountered during the first two treatment cycles, the next patient group was assigned to the next highest dose level until the maximum tolerable dose (MTD) was determined. Results: Twenty-seven patients entered treatment. The majority of non-DLT were grades 1 and 2. DLT experienced in the first 8-week observation period were grade 3 diarrhea (one patient, level III) and grade 3 emesis (two patients, level V). MTD was observed at level 5, 1331 mg/m2/day capecitabine days 1–28 with 125 mg/m2/day cyclophosphamide days 1–14 of the 28-day cycle. The recommended phase II dose is therefore 1331 mg/m2/day capecitabine with 100 mg/m2/day cyclophosphamide. The best response evaluation showed four partial responses (breast, colon, ovary and pancreas). Conclusion: Cyclophosphamide and capecitabine can be combined at their full oral single agent dose with promising tolerability and activity.

Development of microfluidic-based analytical methodology for studying the effects of chemotherapy agents on cancer tissue

Whilst a multitude of techniques have been employed to study the biology of tumour tissue and its response to chemotherapeutic reagents, most current methodologies do not capture the sophistication of the in vivo environment. Microfluidics however offers the ability to maintain and interrogate primary tissue samples in an environment with biomimetic flow characteristics. In this study head and neck squamous cell carcinoma (HNSCC) tumour biopsies have been used to investigate the performance of a microfluidic device for generating clinically-useful information. The response of fresh and cryogenically-frozen primary HNSCC or metastatic lymph node samples to chemotherapy drugs (cisplatin, 5-flurouracil or docetaxel), alone and in combination, were monitored for both proliferation (water-soluble tetrazolium salt metabolism) and cell death biomarker release (lactate dehydrogenase, LDH) “off-chip”. The frozen tissue showed no significant difference in terms of either proliferation or LDH release in comparison with the matched fresh samples. Administration of all drugs caused cell death, in a dose-response manner, with the combination showing the greatest amount of cytotoxicity particularly at days 8 and 9; correlating well with published clinical data. The system described here offers an innovative method for studying the tumour microenvironment in vitro and, through incorporation of relevant analytical modules, provides the basis of a pre-clinical device that can be used to define personalised treatment regimens.

'Iron-saturated' lactoferrin is a potent natural adjuvant for augmenting cancer chemotherapy

Bovine lactoferrin (bLf), an iron-containing natural defence protein found in bodily secretions, has been reported to inhibit carcinogenesis and the growth of tumours. Here, we investigated whether natural bLf and iron-saturated forms of bLf differ in their ability to augment cancer chemotherapy. bLf was supplemented into the diet of C57BL/6 mice that were subsequently challenged subcutaneously with tumour cells, and treated by chemotherapy. Chemotherapy eradicated large (0.6 cm diameter) EL-4 lymphomas in mice that had been fed iron-saturated bLf (here designated Lf(+)) for 6 weeks prior to chemotherapy, but surprisingly not in mice that were fed lesser iron-saturated forms of bLf, including apo-bLf (4% iron saturated), natural bLf (approximately 15% iron saturated) and 50% iron-saturated bLf. Lf(+)-fed mice bearing either EL-4, Lewis lung carcinoma or B16 melanoma tumours completely rejected their tumours within 3 weeks following a single injection of either paclitaxel, doxorubicin, epirubicin or fluorouracil, whereas mice fed the control diet were resistant to chemotherapy. Lf(+) had to be fed to mice for more than 2 weeks prior to chemotherapy to be wholly effective in eradicating tumours from all mice, suggesting that it acts as a competence factor. It significantly reduced tumour vascularity and blood flow, and increased antitumour cytotoxicity, tumour apoptosis and the infiltration of tumours by leukocytes. Lf(+) bound to the intestinal epithelium and was preferentially taken up within Peyer's patches. It increased the production of Th1 and Th2 cytokines within the intestine and tumour, including TNF, IFN-gamma, as well as nitric oxide that have been reported to sensitize tumours to chemotherapy. Importantly, it restored both red and white peripheral blood cell numbers depleted by chemotherapy, potentially fortifying the mice against cancer. In summary, bLf is a potent natural adjuvant and fortifying agent for augmenting cancer chemotherapy, but needs to be saturated with iron to be effective.

A cell-permeable dominant-negative survivin protein induces apoptosis and sensitizes prostate cancer cells to TNF-α therapy

BACKGROUND: Survivin is a member of the inhibitor-of-apoptosis (IAP) family which is widely expressed by many different cancers. Overexpression of survivin is associated with drug resistance in cancer cells, and reduced patient survival after chemotherapy and radiotherapy. Agents that antagonize the function of survivin hold promise for treating many forms of cancer. The purpose of this study was to investigate whether a cell-permeable dominant-negative survivin protein would demonstrate bioactivity against prostate and cervical cancer cells grown in three dimensional culture.

RESULTS: A dominant-negative survivin (C84A) protein fused to the cell penetrating peptide poly-arginine (R9) was expressed in E. coli and purified by affinity chromatography. Western blot analysis revealed that dNSurR9-C84A penetrated into 3D-cultured HeLa and DU145 cancer cells, and a cell viability assay revealed it induced cancer cell death. It increased the activities of caspase-9 and caspase-3, and rendered DU145 cells sensitive to TNF-α via by a mechanism involving activation of caspase-8.

CONCLUSIONS: The results demonstrate that antagonism of survivin function triggers the apoptosis of prostate and cervical cancer cells grown in 3D culture. It renders cancer cells sensitive to the proapoptotic affects of TNF-α, suggesting that survivin blocks the extrinsic pathway of apoptosis. Combination of the biologically active dNSurR9-C84A protein or other survivin antagonists with TNF-α therapy warrants consideration as an approach to cancer therapy.

Clinical and economic burden of emergency department presentations for neutropenia following outpatient chemotherapy for cancer in Victoria, Australia

Objective. To examine the clinical characteristics and financial charges associated with treating adult cancer patients receiving chemotherapy in outpatient clinics who presented to the emergency department (ED) with neutropenia.
Design and Setting. A retrospective audit was conducted across two health services involving ED episodes and subsequent hospital admissions of patients who received chemotherapy through day oncology from January 1 to December 31, 2007 and presented to the ED with neutropenia. ED data were collected from the Victorian Emergency Minimum Dataset and charges were collected from Health Information Services. Descriptive and bivariate statistics were used to describe the patient and clinical characteristics and financial outcomes, and to explore associations between these factors.
Results. In total, 200 neutropenic episodes in 159 outpatients were seen in the ED over the survey period. The mean patient age was 56.6 years (standard deviation, 13.2 years) and 47.2% were male. Overall, 70.0% of ED episodes were triaged as Australasian Triage Scale 2 (emergency). The median ED wait time was 10 minutes and the median ED length of stay was 6.8 hours. The median charge for each ED episode was $764.08 Australian dollars. The total combined ED and inpatient charge per episode was in the range of $144.27-$174,732.68, with a median charge of $5,640.87.
Conclusions. This study provides important insights into the clinical and economic burden of neutropenia from both the ED and inpatient perspectives. Alternative treatment models, such as outpatient treatment, early discharge programs or prophylactic interventions to reduce the clinical and economic burden of neutropenia on our health system, must be explored.

The role of informal caregivers during cancer patients’ recovery from chemotherapy

Aims:  (i) To investigate the availability, perceived importance and roles of informal caregivers in the recovery of patients treated at day oncology centres and (ii) identify differences between patients with and without informal caregivers in the extent to which they experienced symptoms, and the level of bother symptoms caused.

Method:  Patients from three Australian hospitals (n = 122) were recruited during cycles 1 or 2 of adjuvant chemotherapy. Participants completed a modified version of the Rotterdam Symptom Checklist (RSCL) each day for 5 days after chemotherapy. A telephone interview conducted 10 days post-treatment explored the availability, importance and roles of caregivers. During the interview, participants also completed the modified RSCL in which they were asked about the extent to which they experienced, and were bothered by, each symptom over the prior 5 days combined.

Results:  Overall, 71% of participants had an informal caregiver in the 5 days postchemotherapy, commonly a partner. More women (71%) than men (48%) had a caregiver (p < 0.05). Caregivers were perceived to be highly important; they were more important for women than men (U = 213.50, p < 0.01). The most common assistance caregivers provided was meal preparation and emotional support and companionship. On days 6–10 postchemotherapy, the extent to which overall physical symptoms were experienced was higher for patients with a caregiver than without (U = 987.50, p < 0.05); similarly their symptoms caused more bother (U = 966.00, p < 0.01).

Conclusions:  These findings highlighted the importance of informal caregivers to patients postchemotherapy. It is imperative that patients are informed of the importance of this support so a caregiver can be arranged, if possible. Understanding the needs of patients following chemotherapy would enable health professionals to advise patients, with or without caregivers, how to best prepare for and manage their recovery at home.

Anti-angiogenic therapy for lung cancer

This is the protocol for a review and there is no abstract. The objectives are as follows:

To determine the benefits and harms of angiogenesis inhibitors in the treatment of lung cancer when given alone, following or in combination with chemotherapy or chemo-radiotherapy (in the case of locally advanced non-metastatic NSCLC or limited stage SCLC).