A feasibility, safety, and efficacy evaluation of supervised aerobic and resistance exercise for patients with glioblastoma undertaking adjuvant chemoradiotherapy.

Background: While therapeutically effective, chemoradiotherapy treatment for high-grade glioma (glioblastoma) is often accompanied by side effects. Exercise has been demonstrated to alleviate the adverse effects of such treatments in other cancers. We aimed to evaluate the feasibility and preliminary efficacy of supervised exercise incorporating autoregulation. Methods: Thirty glioblastoma patients were recruited, five declined exercise and 25 were provided with a multimodal exercise intervention for the duration of their chemoradiotherapy treatment. Patient recruitment, retention, adherence to training sessions and safety were evaluated throughout the study. Physical function, body composition, fatigue, sleep quality, and quality of life were evaluated before and after the exercise intervention. Results: Eight of the 25 participants commencing exercise withdrew prior to completion of the study (32%). Seventeen patients (68%) demonstrated low to high adherence (33%-100%) and exercise dosage compliance (24%-83%). There were no reported adverse events. Significant improvements were observed for all trained exercises and lower limb muscle strength and function with no significant changes observed for any other physical function, body composition, fatigue, sleep, or quality of life outcomes. Conclusions: Only half of glioblastoma patients recruited were willing or able to commence, complete or meet minimum dose compliance for the exercise intervention during chemoradiotherapy indicating the intervention evaluated may not be feasible for part of this patient cohort. For those who were able to complete the exercise program, supervised, autoregulated, multimodal exercise was safe and significantly improved strength and function and may have prevented deterioration in body composition and quality of life.

Real-World Outcomes of Ribociclib and Aromatase Inhibitor Use in First Line Hormone Receptor Positive, HER2-Negative Metastatic Breast Cancer.

BACKGROUND: International guidelines recommend combining a CDK4/6 inhibitor and endocrine therapy (ET) as first line treatment for hormone receptor (HR) positive, HER2 negative metastatic breast cancer (MBC). Results from MONALEESA-2 demonstrate superior progression free survival (PFS) and overall survival (OS) with ribociclib (CDK4/6 inhibitor) and ET compared to ET alone. Real world outcomes have yet to be reported. MATERIALS AND METHODS: KARMA is a non-interventional registry of Australian patients receiving first-line treatment with ribociclib and aromatase inhibitor (AI), obtained via a Medicine Access Program (MAP) for HR+, HER2- MBC. Outcomes were compared with the ribociclib/letrozole cohort in MONALEESA-2. RESULTS: Data from 160 patients at 17 sites was analysed. Median follow-up is 36.5 months. Compared to MONALEESA-2, patients were numerically younger (54.3 vs. 62 years), with higher rates of bone-only metastases (31% vs. 21%). A total of 63 of 160 (39%) patients remain on treatment. A total of 56% of patients had at least 1 dose reduction, with neutropenia (68%) and abnormal liver enzymes (17%) the most common reasons. A total of 17 of 160 (11%) discontinued treatment due to toxicity, with no treatment related deaths. Median PFS was not reached (95% CI 29.9- NR), with PFS at 12 months and 18 months being 76% and 67% respectively versus 25.3 months, 73% and 63% in MONALEESA-2. CONCLUSION: The ribociclib and AI combination was well tolerated in this real-world setting. The KARMA registry cohort achieved a superior PFS (>36.5 months) to MONALEESA-2, potentially due to more favourable baseline disease characteristics. Less frequent assessment scheduling in this non trial setting may also contribute.

Incorporation of eribulin in the systemic treatment of metastatic breast cancer patients in Australia.

PURPOSE: Review of utilization and efficacy of eribulin in Australian metastatic breast cancer (MBC) patients. METHODS: Retrospective review of consecutive MBC patients treated with eribulin in tertiary Australian BC centers. Key inclusion criteria included eribulin administration in nonclinical trial setting from October 2014 onwards, known duration of MBC systemic treatments administered and known follow-up date after eribulin. Cox regression model was used to assess survival. RESULTS: Study population comprised 266 patients from eight centers treated between October 2014 and May 2018. Median age at time of MBC diagnosis was 54 years with 18% of patients having de novo MBC. Seventy-six percent had hormone receptor positive (HRp) disease, 19% triple negative (TN) and 5% HER2-positive. CNS involvement was present in 36% of patients. Eribulin was most frequently given as third-line chemotherapy (36%), with no prior anthracycline exposure in 14% of total population. Eribulin was given more frequently as ≤third-line chemotherapy than > third-line in patients with TN disease, ≥ two metastatic sites or CNS disease. Median overall survival (OS) from eribulin administration was 9.2 (95% CI [8.0, 10.3]) months. CONCLUSION: Similar efficacy was demonstrated for eribulin when given in the first-line to beyond the fifth line of chemotherapy in all subtypes of MBC.

Afatinib in EGFR TKI-naïve patients with locally advanced or metastatic EGFR mutation-positive non-small cell lung cancer: Interim analysis of a Phase 3b study.

OBJECTIVES: Randomized controlled trials have demonstrated that afatinib is a suitable treatment option for patients with epidermal growth factor receptor mutation-positive (EGFRm +) non-small cell lung cancer (NSCLC). However, such studies often exclude patients treated in routine clinical practice. We report interim results from a Phase 3b, open-label, multicenter, single-arm, exploratory trial, in which afatinib was investigated in a real-world setting. MATERIALS AND METHODS: Patients with EGFRm + tyrosine kinase inhibitor (TKI)-naïve NSCLC received afatinib 40 mg orally, once-daily, until disease progression, or voluntary withdrawal. Primary objective was safety. RESULTS: Overall, 479 patients received afatinib: median age 65 years, 8 % of patients had an ECOG performance status ≥ 2, 17 % had brain metastases, and 13 % had tumors containing uncommon mutations only. All but one patient (99.8 %) had an adverse event (AE). Treatment-related AEs (TRAEs; any/grade ≥ 3) occurred in 97 %/44 % of patients; most common were diarrhea (87 %/16 %) and rash (51 %/11 %). AEs leading to afatinib dose-reduction were reported in 258 patients (54 %), and 37 patients (8 %) discontinued treatment due to a TRAE. Objective response rate was 45.5 %, median duration of response was 14.1 months (95 % CI: 12.2-16.4). Overall median time to symptomatic progression and progression-free survival were 14.9 months (95 % CI: 13.8-17.6) and 13.4 months (95 % CI: 11.8-14.5), respectively, in the overall population and 19.3 months (95 % CI: 15.6-21.8) and 15.9 months (95 % CI: 13.9-19.1) in patients with EGFR exon 19 deletions. CONCLUSIONS: Afatinib administration in routine clinical practice was well tolerated with no new safety signals and demonstrated promising efficacy in patients with EGFRm + NSCLC. TRAEs were generally manageable with tolerability-guided dose reductions. Overall, these data independently support findings from randomized controlled trials of afatinib in EGFRm + NSCLC.

Mechanical suppression of osteolytic bone metastases in advanced breast cancer patients: a randomised controlled study protocol evaluating safety, feasibility and preliminary efficacy of exercise as a targeted medicine.

BACKGROUND: Skeletal metastases present a major challenge for clinicians, representing an advanced and typically incurable stage of cancer. Bone is also the most common location for metastatic breast carcinoma, with skeletal lesions identified in over 80% of patients with advanced breast cancer. Preclinical models have demonstrated the ability of mechanical stimulation to suppress tumour formation and promote skeletal preservation at bone sites with osteolytic lesions, generating modulatory interference of tumour-driven bone remodelling. Preclinical studies have also demonstrated anti-cancer effects through exercise by minimising tumour hypoxia, normalising tumour vasculature and increasing tumoural blood perfusion. This study proposes to explore the promising role of targeted exercise to suppress tumour growth while concomitantly delivering broader health benefits in patients with advanced breast cancer with osteolytic bone metastases. METHODS: This single-blinded, two-armed, randomised and controlled pilot study aims to establish the safety, feasibility and efficacy of an individually tailored, modular multi-modal exercise programme incorporating spinal isometric training (targeted muscle contraction) in 40 women with advanced breast cancer and stable osteolytic spinal metastases. Participants will be randomly assigned to exercise or usual medical care. The intervention arm will receive a 3-month clinically supervised exercise programme, which if proven to be safe and efficacious will be offered to the control-arm patients following study completion. Primary endpoints (programme feasibility, safety, tolerance and adherence) and secondary endpoints (tumour morphology, serum tumour biomarkers, bone metabolism, inflammation, anthropometry, body composition, bone pain, physical function and patient-reported outcomes) will be measured at baseline and following the intervention. DISCUSSION: Exercise medicine may positively alter tumour biology through numerous mechanical and non-mechanical mechanisms. This randomised controlled pilot trial will explore the preliminary effects of targeted exercise on tumour morphology and circulating metastatic tumour biomarkers using an osteolytic skeletal metastases model in patients with breast cancer. The study is principally aimed at establishing feasibility and safety. If proven to be safe and feasible, results from this study could have important implications for the delivery of this exercise programme to patients with advanced cancer and sclerotic skeletal metastases or with skeletal lesions present in haematological cancers (such as osteolytic lesions in multiple myeloma), for which future research is recommended. TRIAL REGISTRATION: anzctr.org.au , ACTRN-12616001368426 . Registered on 4 October 2016.

Management of patients treated with pertuzumab in the Australian clinical practice setting.

AIM: Treatment with pertuzumab-trastuzumab-taxane combinations has become the international standard of care for patients with HER2-positive metastatic breast cancer. In this paper we discuss the practicalities of treating patients with this combination with a particular focus on treatment in the Australian setting. METHOD: An expert panel was convened to discuss practical aspects for use of pertuzumab in the Australian clinical setting. The findings of this panel are reported in this article. RESULTS: The combination of pertuzumab-trastuzumab-docetaxel has established efficacy in patients with HER2-positive metastatic breast cancer, prolonging progression-free and overall survival compared to trastuzumab-taxane combinations. In Australia, combinations of pertuzumab and trastuzumab with docetaxel or paclitaxel are reimbursed. Management of treatment related side-effects such as diarrhea, febrile neutropenia and neuropathy typically include dose reduction or switching taxane. Specific patients with poorer tolerance of chemotherapy such as the elderly or those from Asian backgrounds may require particular management strategies. CONCLUSIONS: The advent of targeted therapies for women with metastatic HER2-positive breast cancer has markedly improved survival. Combinations of pertuzumab-trastuzumab and a taxane are the standard of care in patients with good performance status. Given prolongation of survival and the importance of quality of life endpoints, the treatment paradigm for patients with metastatic HER2-positive breast cancer is changing rapidly. Careful management of toxicities is required, and dose reduction or switching taxane may be necessary. Further research is required on the efficacy of pertuzumab combinations in patients with brain metastases, and on those who relapse quickly following adjuvant therapy.

Exercise Improves Physical Function and Mental Health of Brain Cancer Survivors: Two Exploratory Case Studies.

Background Malignant brain tumors are unpredictable and incurable, with 5-year survival rates less than 30%. The poor prognosis combined with intensive treatment necessitates the inclusion of complementary and supportive therapies that optimize quality of life and reduce treatment-related declines in health. Exercise therapy has been shown to be beneficial in other cancer populations, but no evidence is available for brain cancer survivors. Therefore, we report results from 2 preliminary cases. Methods Two female patients diagnosed with glioblastoma multiforme and oligodendroglioma participated in a structured and supervised 12-week exercise program. The program consisted of two 1-hour resistance and aerobic exercise sessions per week and additional self-managed aerobic sessions. Outcome measures of strength, cardiovascular fitness, and several psychological indicators (depression, anxiety, and quality of life) were recorded at baseline, after 6 weeks and at the conclusion of the intervention. Results Exercise was well tolerated; both participants completed all 24 sessions and the home-based component with no adverse effects. Objective outcome measures displayed positive responses relating to reduced morbidity. Similar positive responses were found for psychological outcomes. Scores on the Hospital Anxiety and Depression Scale showed clinically meaningful improvements in depression and total distress. Conclusion These findings provide initial evidence that, despite the difficulties associated with brain cancer treatment and survivorship, exercise may be safe and beneficial and should be considered in the overall management of patients with brain cancer.

Acute disseminated intravascular coagulation in neuroendocrine carcinoma.

Malignancy is a common cause of disseminated intravascular coagulation and usually presents as a chronic disorder in solid organ tumours. We present a rare case of recurrent acute disseminated intravascular coagulation in neuroendocrine carcinoma after manipulation, firstly, by core biopsy and, later, by cytotoxic therapy causing a release of procoagulants and cytokines from lysed tumour cells. This is reminiscent of tumour lysis syndrome where massive quantities of intracellular electrolytes and nucleic acid are released, causing acute metabolic imbalance and renal failure. This case highlights the potential complication of acute disseminated intravascular coagulation after trauma to malignant cells.

Willingness of breast cancer survivors to participate in a randomized controlled trial of digital mammography with or without MRI as breast cancer surveillance: a feasibility study.

Breast MRI is often used for surveillance of breast cancer (BC) survivors despite the lack of evidence in this population. We surveyed younger BC survivors to evaluate their willingness to participate in a randomized controlled trial (RCT) of annual digital mammography with or without MRI. Median age of the 348 participants was 51 years; 45% had undergone diagnostic MRI. 22% continued to have surveillance MRI. 58% agreed to consider participating in the proposed RCT; 16% remained neutral. An RCT of MRI surveillance for BC survivors

Cost-effectiveness analysis of recurrence score-guided treatment using a 21-gene assay in early breast cancer.

PURPOSE: Most guidelines for hormone receptor (HR)-positive early breast cancer recommend addition of adjuvant chemotherapy for most women, leading to overtreatment, which causes considerable morbidity and cost. There has been recent incorporation of gene expression analysis in aiding decision making. We evaluated the cost-effectiveness of recurrence score (RS)-guided treatment using 21-gene assay as compared with treatment guided by the Adjuvant! Online program (AOL). PATIENTS AND METHODS: A Markov model was developed to compare the cost-effectiveness of treatment guided either by 21-gene assay or by AOL in a 50-year-old woman with lymph node-negative HR-positive breast cancer over a lifetime horizon. We assumed that women classified to be at high risk all received chemotherapy followed by tamoxifen and those classified to be at low risk received tamoxifen only. The model took a health care payer's perspective with results reported in 2008 Canadian dollars ($). Event rates, costs, and utilities were derived from the literature. Both costs and benefits were discounted at 5%. Outcome measures were life years gained, quality-adjusted life years (QALYs), lifetime costs, and incremental cost-effectiveness ratios (ICERs). RESULTS: For a 50-year-old woman, RS-guided treatment was associated with an incremental lifetime cost of $4,102 and a gain in 0.065 QALY, with an ICER of $63,064 per QALY compared with AOL-guided treatment. ICER increased with increasing cost of 21-gene assay and increasing age of patients. Results were most sensitive to probabilities relating to risk categorization and recurrence rate. CONCLUSIONS: The 21-gene assay appears cost-effective from a Canadian health care perspective.

Review of the clinical studies using the 21-gene assay.

PURPOSE: A major challenge in treating early-stage hormone receptor (HR)(+) breast cancer is selecting women who, after initial surgery, do not require chemotherapy. Better prognostic and predictive tests are needed. The 21-gene assay is the only widely commercially available gene signature that can be performed on formalin-fixed paraffin-embedded tissue. METHODS: We conducted a review of the literature supporting the prognostic and predictive ability of the 21-gene assay in HR(+) node-negative and node-positive breast cancer patients in chemotherapy-/endocrine-treated and untreated populations. We considered: (a) How accurate is the recurrence score (RS) as a prognostic factor for distant recurrence? (b) How accurate is the RS as a predictive factor for benefit from systemic therapy? (c) How does the RS compare with other prognostic/predictive factors such as tumor size, tumor grade, patient age, and integrated decision aids such as Adjuvant! Online? (d) How do patients and physicians view the 21-gene assay? (e) What are the cost implications of the 21-gene assay? RESULTS: The 21-gene assay: (a) provided accurate risk information; (b) predicted response to cyclophosphamide, methotrexate, and 5-fluorouracil and to cyclophosphamide, doxorubicin, and 5-fluorouracil chemotherapy; (c) added additional information to traditional biomarkers; (d) was viewed positively by both physicians and patients; and (e) fell within the cost-effectiveness values in North America. CONCLUSION: This assay may be offered to patients with node-negative HR(+) breast cancer to assist in adjuvant treatment decisions. Data are accumulating to support the use of the 21-gene assay in HR(+) node-positive patients.

Gastric adenocarcinoma presenting as uterine metastasis--a case report.

BACKGROUND: Metastases to the uterus are rare, especially from extrapelvic malignancies. CASE: We report a 75-year-old woman who underwent hysterectomy for a FIGO Grade I endometrial carcinoma and was found to have evidence of a second malignant process involving the myometrium. The patient underwent a gastroscopy, which showed nonspecific superficial gastric and duodenal erosions. Random biopsies, however, confirmed a diagnosis of primary gastric adenocarcinoma. CT scan also showed pulmonary metastasis. The patient developed progressive disease despite two cycles of chemotherapy consistent of etoposide, doxorubicin and carboplatin. CONCLUSION: This case illustrates the presence of two spatially separated tumours found in the uterus. Malignant cells present deep in the lymphovascular spaces have morphological features different from the primary endometrial carcinoma. The microscopic appearances of these cells are similar to that of the gastric biopsy, supporting the diagnosis of metastatic gastric adenocarcinoma.