Individual or combination treatments with lapatinib and paclitaxel cause potential bone loss and bone marrow adiposity in rats.

Cancer treatments with cytotoxic drugs have been shown to cause bone loss. However, effects on bone are less clear for ErbB-targeting tyrosine kinase inhibitors or their combination use with cytotoxic drugs. This study examined the effects of individual or combination treatments with breast cancer drugs lapatinib (a dual ErbB1/ErbB2 inhibitor) and paclitaxel (a microtubule-stabilizing cytotoxic agent) on bone and bone marrow of rats. Wistar rats received lapatinib (240 mg/kg) daily, paclitaxel (12 mg/kg) weekly, or their combination for 4 weeks, and effects on bone/bone marrow were examined at the end of week 4. Microcomputed tomographical structural analyses showed a reduction in trabecular bone volume in tibia following the lapatinib, paclitaxel or their combination treatments ( P < 0.05). Histomorphometry analyses revealed marked increases in bone marrow adipocyte contents in all treatment groups. Reverse transcription polymerase chain reaction gene expression studies with bone samples and cell culture studies with isolated bone marrow stromal cells showed that the all treatment groups displayed significantly reduced levels of osterix expression and osteogenic differentiation potential but increased expression levels of adipogenesis transcription factor peroxisome proliferator-activated receptor γ. In addition, these treatments suppressed the expression of Wnt10b and/or increased expression of Wnt antagonists (secreted frizzled-related protein 1, Dickkopf-related protein 1 and/or sclerostin). Furthermore, all treatment groups showed increased numbers of bone-resorbing osteoclasts on trabecular bone surfaces, although only the lapatinib group displayed increased levels of osteoclastogenic signal (receptor activator of nuclear factor κΒ ligand/osteoclastogenesis inhibitor osteoprotegrin expression ratio) in the bones. Thus, inhibiting ErbB1 and ErbB2 by lapatinib or blocking cell division by paclitaxel or their combination causes significant trabecular bone loss and bone marrow adiposity involving a switch in osteogenesis/adipogenesis potential, altered expression of some major molecules of the Wnt/ß-catenin signalling pathway, and increased recruitment of bone-resorbing osteoclasts.

Dacomitinib-induced diarrhea: Targeting chloride secretion with crofelemer.

Dacomitinib, an irreversible small-molecule pan-ErbB TKI, has a high incidence of diarrhea, which has been suggested to be due to chloride secretory mechanisms. Based on this hypothesis, crofelemer, an antisecretory agent may be an effective intervention. T84 monolayers were treated with 1 µM dacomitinib and 10 µM crofelemer, and mounted into Ussing chambers for electrogenic ion analysis. Crofelemer attenuated increases in chloride secretion in cells treated with dacomitinib. Albino Wistar rats (n = 48) were treated with 7.5 mg/kg dacomitinib and/or 25 mg/kg crofelemer via oral gavage for 21 days. Crofelemer significantly worsened dacomitinib-induced diarrhea (p = 0.0003), and did not attenuate weight loss (p < 0.0001). Sections of the ileum and colon were mounted into Ussing chambers, and secretory processes analyzed. This indicated that crofelemer lost its anti-secretory action in the presence of dacomitinib in this model. Mass spectrometry revealed that crofelemer did not change serum concentration of dacomitinib. Serum FITC dextran levels indicated that crofelemer was unable to attenuate dacomitinib-induced barrier dysfunction. Tight junction proteins were visualized with immunofluorescence. Qualitative analysis showed dacomitinib induced proteolysis of ZO-1 and occludin, and internalization of claudin-1, which was not attenuated by crofelemer. Detailed histopathological analysis showed that crofelemer was unable to attenuate dacomitinib-induced ileal damage. Crofelemer worsened dacomitinib-induced diarrhea, suggesting that antisecretory drug therapy may be ineffective in this setting.

Matrix metalloproteinase expression is altered in the small and large intestine following fractionated radiation in vivo.

PURPOSE: Radiotherapy-induced gut toxicity (RIGT) is associated with significant diarrhoea, pain and rectal bleeding. Matrix metalloproteinases (MMPs) have been reported to be involved in chemotherapy-induced gut toxicity and RIGT following single-dose irradiation in vivo. We therefore proposed MMPs would be involved in the pathobiology of RIGT following fractionated irradiation. METHODS: Dark Agouti rats were treated with fractionated radiation (3 × 2.5 Gy/week for 6 weeks). Rats were killed at 3, 6 and 15 weeks to represent acute and chronic toxicities. Sections of jejunum and colon were immunostained for MMP-1, MMP-2, MMP-9 and MMP-14. Relative mRNA expression in jejunum and colon was quantified by RT-PCR for MMP-1, MMP-2, MMP-9 and MMP-14. Western blotting was also conducted on jejunum and colon tissue collected at week 6 to determine protein levels of pro- and active MMP-2. RESULTS: MMP-2 total protein levels, determined by western blotting, significantly increased in both the jejunum (p = 0.0359) and the colon (p = 0.0134) 6 weeks into the fractionated radiation schedule. MMP-1, MMP-2, and MMP-14 mRNA expression significantly increased in the jejunum. MMP-2 mRNA expression was also significantly increased in the colon. Immunostaining of MMP-2 was observed to be increased in both crypt enterocytes and the lamina propria. CONCLUSIONS: MMP-2 plays a role in the pathobiology of gastrointestinal toxicities following fractionated irradiation. Whilst MMP-1 and MMP-14 mRNA expression was increased, this occurred only in the jejunum, suggesting MMPs are differentially involved in RIGT depending on the intestinal region. Further studies are needed to elucidate the role these mediators play in the development and potentiation of RIGT.

Dacomitinib-induced diarrhoea is associated with altered gastrointestinal permeability and disruption in ileal histology in rats.

Dacomitinib-an irreversible pan-ErbB tyrosine kinase inhibitor (TKI)-causes diarrhoea in 75% of patients. Dacomitinib-induced diarrhoea has not previously been investigated and the mechanisms remain poorly understood. The present study aimed to develop an in-vitro and in-vivo model of dacomitinib-induced diarrhoea to investigate underlying mechanisms. T84 cells were treated with 1-4 µM dacomitinib and resistance and viability were measured using transepithelial electrical resistance (TEER) and XTT assays. Rats were treated with 7.5 mg/kg dacomitinib daily via oral gavage for 7 or 21 days (n = 6/group). Weights, and diarrhoea incidence were recorded daily. Rats were administered FITC-dextran 2 hr before cull, and serum levels of FITC-dextran were measured and serum biochemistry analysis was conducted. Detailed histopathological analysis was conducted throughout the gastrointestinal tract. Gastrointestinal expression of ErbB1, ErbB2 and ErbB4 was analysed using RT-PCR. The ileum and the colon were analysed using multiplex for expression of various cytokines. T84 cells treated with dacomitinib showed no alteration in TEER or cell viability. Rats treated with dacomitinib developed severe diarrhoea, and had significantly lower weight gain. Further, dacomitinib treatment led to severe histopathological injury localised to the ileum. This damage coincided with increased levels of MCP1 in the ileum, and preferential expression of ErbB1 in this region compared to all other regions. This study showed dacomitinib induces severe ileal damage accompanied by increased MCP1 expression, and gastrointestinal permeability in rats. The histological changes were most pronounced in the ileum, which was also the region with the highest relative expression of ErbB1.

Combination breast cancer chemotherapy with doxorubicin and cyclophosphamide damages bone and bone marrow in a female rat model.

PURPOSE: Anthracyclines (including doxorubicin) are still the backbone of commonly used breast cancer chemotherapy regimens. Despite increasing use of doxorubicin and cyclophosphamide (AC) combinations for treating breast cancer, their potential to cause adverse skeletal effects remains unclear. METHODS: This study examined the effects of treatments with the AC regimen on bone and bone marrow in adult female rats. RESULTS: AC treatment for four cycles (weekly intravenous injection of 2 mg/kg doxorubicin and 20 mg/kg cyclophosphamide) resulted in a reduced volume of trabecular bone at the metaphysis, which was associated with reduced serum levels of 25-hydroxy vitamin D3 and alkaline phosphatase. Reductions in densities of osteocytes and bone lining cells were also observed. In addition, bone marrow was severely damaged, including a severe reduction in bone marrow cellularity and an increase in marrow adipocyte content. Accompanying these changes, there were increases in mRNA expression of adipogenesis regulatory genes (PPARγ and FABP4) and an inflammatory cytokine (TNFα) in metaphysis bone and bone marrow. CONCLUSIONS: This study indicates that AC chemotherapy may induce some bone loss, due to reduced bone formation, and bone marrow damage, due to increased marrow adiposity. Preventive strategies for preserving the bone and bone marrow microenvironment during anthracycline chemotherapy warrant further investigation.

Fractionated abdominal irradiation induces intestinal microvascular changes in an in vivo model of radiotherapy-induced gut toxicity.

PURPOSE: Radiotherapy-induced gut toxicity (RIGT) is associated with diarrhoea, pain and rectal bleeding and can occur as an acute or chronic toxicity. The microvasculature has been shown to be altered in the development of RIGT; however, the features are not yet characterized. We hypothesized that apoptosis of microvascular cells would occur early in the gastrointestinal tract following fractionated irradiation, followed by late microvascular changes, including sclerosis and telangiectasis. METHODS: Female Dark Agouti rats were treated with a 6-week fractionated radiation schedule of 3 × 2.5 Gy doses per week localized to the abdomen. At 3, 6 and 15 weeks, the intestines were assessed for markers of acute and chronic injury including morphological changes, collagen deposition, apoptosis and proliferation. RESULTS: Apoptosis of microvascular cells significantly increased at 6 and 15 weeks in the jejunum (p = 0.0026 and p = 0.0062, respectively) and at 6 and 15 weeks in the colon (p < 0.0001 and p = 0.0005, respectively) in rats receiving fractionated radiation to the abdomen. Histopathological changes of the colon microvasculature were also seen from week 3, including thickening of the lamina propria and dilated, thickened, telangiectatic vessels. CONCLUSIONS: Findings of this study provide evidence of regional and timing-specific changes in the intestinal microvasculature in response to fractionated radiotherapy which may play a role in development of both acute and chronic RIGT.

Combination chemotherapy with cyclophosphamide, epirubicin and 5-fluorouracil causes trabecular bone loss, bone marrow cell depletion and marrow adiposity in female rats.

The introduction of anthracyclines to adjuvant chemotherapy has increased survival rates among breast cancer patients. Cyclophosphamide, epirubicin and 5-fluorouracil (CEF) combination therapy is now one of the preferred regimens for treating node-positive breast cancer due to better survival with less toxicity involved. Despite the increasing use of CEF, its potential in causing adverse skeletal effects remains unclear. Using a mature female rat model mimicking the clinical setting, this study examined the effects of CEF treatment on bone and bone marrow in long bones. Following six cycles of CEF treatment (weekly intravenous injections of cyclophosphamide at 10 mg/kg, epirubicin at 2.5 mg/kg and 5-flurouracil at 10 mg/kg), a significant reduction in trabecular bone volume was observed at the metaphysis, which was associated with a reduced serum level of bone formation marker alkaline phosphatase (ALP), increased trends of osteoclast density and osteoclast area at the metaphysis, as well as an increased size of osteoclasts being formed from the bone marrow cells ex vivo. Moreover, a severe reduction of bone marrow cellularity was observed following CEF treatment, which was accompanied by an increase in marrow adipose tissue volume. This increase in marrow adiposity was associated with an expansion in adipocyte size but not in marrow adipocyte density. Overall, this study indicates that six cycles of CEF chemotherapy may induce some bone loss and severe bone marrow damage. Mechanisms for CEF-induced bone/bone marrow pathologies and potential preventive strategies warrant further investigation.

Management of Mucositis During Chemotherapy: From Pathophysiology to Pragmatic Therapeutics.

Chemotherapy-induced mucositis is a common condition caused by the breakdown of the mucosal barrier. Symptoms can include pain, vomiting and diarrhoea, which can often necessitate chemotherapy treatment breaks or dose reductions, thus compromising survival outcomes. Despite the significant impact of mucositis, there are currently limited clinically effective pharmacological therapies for the pathology. New emerging areas of research have been proposed to play key roles in the development of mucositis, providing rationale for potential new therapeutics for the prevention, treatment or management of chemotherapy-induced mucositis. This review aims to address these new areas of research and to comment on the therapeutics arising from them.

Involvement of matrix metalloproteinases (MMP-3 and MMP-9) in the pathogenesis of irinotecan-induced oral mucositis.

OBJECTIVES: Matrix metalloproteinases (MMPs) are involved in both maintenance of healthy mucosa and mediation of several pathologies. Recently, MMPs and their inhibitors have attracted attention as potential mediators of mucositis. We investigated tissue expression of MMP-3 and MMP-9 over time in a pre-clinical model of irinotecan-induced oral mucositis (OM). MATERIALS AND METHODS: Eighty-one female Dark Agouti rats received either a single dose of irinotecan (200 mg/kg) or vehicle control. Rats were killed at different time points over a 72-h period and tongue mucosa examined histologically. Tissue expression of MMP-3 and MMP-9 was characterized by standard qualitative immunohistochemistry. RESULTS AND DISCUSSION: Epithelial thickness was reduced without any ulceration in the oral mucosa early after chemotherapy. Epithelial atrophy was associated with significant (P < 0.05) upregulation of MMP-3 and MMP-9 in all layers of the oral epithelium. The increase of MMP-3 was also significant (P < 0.05) in lamina propria and submucosa. Most of changes in expression occurred early (1-6 h), coinciding with previously described upregulation of transcription factors and pro-inflammatory cytokines in OM. Tissue expression of MMP-3 and MMP-9 followed different patterns of change over time, suggesting involvement in various aspects of OM pathophysiology. CONCLUSIONS: These findings suggest vital roles played by MMP-3 and MMP-9 during OM pathophysiology. Further research is required to investigate the role of other MMPs and the naturally existing tissue inhibitors of MMPs. Research should also be directed to investigate beneficial effects of MMPs intervention therapies to prevent or reduce the severity of OM.

Impact of CINV in earlier cycles on CINV and chemotherapy regimen modification in subsequent cycles in Asia Pacific clinical practice.

PURPOSE: We sought to describe the impact of chemotherapy-induced nausea and vomiting (CINV) in prior cycles on CINV and chemotherapy regimen modification in subsequent cycles. METHODS: Eligible patients in this multinational prospective observational study were adults (≥18 years old) receiving their first single-day highly or moderately emetogenic chemotherapy (HEC or MEC). Multivariate logistic regression was used to assess the impact of CINV in prior cycles on CINV in subsequent cycles. Other independent variables included in the model were the cycle number, age, sex, and emetogenicity of regimen. RESULTS: There were 598 evaluable patients in cycle 2 and 533 in cycle 3, half receiving HEC and half MEC. Patients who experienced complete response (no emesis or rescue antiemetics) in earlier cycles, relative to those with no complete response, had an adjusted odds ratio (OR) of 5.9 (95% confidence interval (CI), 4.14-8.50) for experiencing complete response in subsequent cycles. Prior CINV was a significant and consistent predictor of subsequent CINV for all CINV endpoints: for emesis, OR 12.7 (95% CI, 8.47-18.9), for clinically significant nausea, OR 7.9 (95% CI, 5.66-10.9), and for clinically significant nausea and/or vomiting, OR 7.2 (5.17-10.1). Modifications to chemotherapy were recorded for 26-29% of patients in cycles 2 and 3, with CINV as the major reason for the modification for 5-9% of these patients. CONCLUSIONS: CINV in prior cycles was a strong and consistent predictor of CINV in subsequent cycles, while the incidence of chemotherapy regimen modification due to CINV was low in individual cycles.

Antiemetic therapy in Asia Pacific countries for patients receiving moderately and highly emetogenic chemotherapy--a descriptive analysis of practice patterns, antiemetic quality of care, and use of antiemetic guidelines.

PURPOSE: This paper reports prescribing patterns for prophylaxis of chemotherapy-induced nausea and vomiting (CINV) after highly or moderately emetogenic chemotherapy (HEC or MEC) for cancer in six Asia Pacific countries. METHODS: In a prospective noninterventional study, 31 sites in Australia, China, India, Singapore, South Korea, and Taiwan recorded details of CINV prophylaxis for the acute phase (first 24 h) and delayed phase (days 2-5) after single-day HEC or MEC for adult patients. Additional information on CINV prophylactic medications was collected from 6-day patient diaries. Primary antiemetic therapies were defined as corticosteroids, the 5-hydroxytryptamine-3 receptor antagonists (5HT3-RAs), and neurokinin-1 receptor antagonists (NK1-RAs). RESULTS: Evaluable patients in cycle 1 numbered 648 (318 [49%] HEC and 330 [51%] MEC) of mean (SD) age of 56 (12) years, including 58% women. For the acute phase after HEC, overall (and country range), 96% (91-100%) of patients received a 5HT3-RA, 87% (70-100%) a corticosteroid, and 43% (0-91%) an NK1-RA. CINV prophylaxis for the HEC delayed phase was more variable: including 22% (7-65%) 5HT3-RA, 52% (12-93%) corticosteroid, and 46% (0-88%) NK1-RA. For the MEC acute phase, 97% (87-100%) of patients received 5HT3-RA and 86% (73-97%) a corticosteroid. For the MEC delayed phase, 201 patients (61%) received a primary antiemetic, including 5HT3-RA (41%), corticosteroid (37%), and/or NK1-RA (4%). CONCLUSIONS: The 5HT3-RAs were prescribed consistently in all countries, while prescribing of other antiemetic therapies was variable, and corticosteroids were under-prescribed for CINV prophylaxis, particularly in the delayed phase.

Rationale and design of the Pan Australasian chemotherapy-induced emesis burden of illness study.

BACKGROUND: Preventing and managing chemotherapy-induced nausea and vomiting (CINV) remain important goals. The objective of the Pan Australasian chemotherapy-induced emesis burden of illness (PrACTICE) study was to describe the incidence of CINV after highly or moderately emetogenic chemotherapy (HEC or MEC) for cancer in current clinical practice in Australia and five Asian countries (China, India, Singapore, South Korea, and Taiwan). STUDY DESIGN: This prospective, observational study of CINV was conducted at 31 sites in these six countries from August 2011 through September 2012 and enrolled male and female adult patients (≥18 years of age) naïve to HEC and MEC who were scheduled to receive at least two cycles of single-day chemotherapy. The primary effectiveness endpoint was complete response, defined as no vomiting or use of rescue therapy, during chemotherapy cycle 1 in the overall phase (0-120 h), acute phase (0-24 h), and delayed phase (>24-120 h). Study outcomes were analyzed descriptively. Primary outcomes, CINV incidence, and treatment patterns (chemotherapy, CINV prophylaxis, rescue medication prescription, and rescue medication use) were assessed by phase (overall, acute, delayed), by cycle (as appropriate), within and across countries, and by level of chemotherapy emetogenicity (HEC vs. MEC). The impact of CINV in cycle 1 on CINV in cycle 2 was analyzed for all patients with evaluable data for cycle 2. No site-specific analyses were performed. The remainder of this special series of papers reports on the results of this study.

Incidence and predictors of anticipatory nausea and vomiting in Asia Pacific clinical practice--a longitudinal analysis.

PURPOSE: Some patients experience nausea and/or vomiting (NV) before receipt of chemotherapy. Our objective was to evaluate the impact of prior chemotherapy-induced NV (CINV) on the incidence of anticipatory NV in later cycles. METHODS: This multicenter, prospective non-interventional study enrolled chemotherapy-naïve adults scheduled to receive highly or moderately emetogenic chemotherapy (HEC/MEC) for cancer in six Asia Pacific countries, excluding those with emesis within 24 h before cycle 1 chemotherapy. On day 1 before chemotherapy, patients answered four questions regarding emesis in the past 24 h, nausea, expectation of post-chemotherapy nausea, and anxiety in the past 24 h, the latter three scored from 0-10 (none-maximum). Multivariate logistic regression was used to assess the impact of prior CINV on anticipatory NV in cycles 2 and 3. RESULTS: Five hundred ninety-eight patients (59% female) were evaluable in cycle 2 (49% HEC, 51% MEC). The incidence of anticipatory emesis was low before cycles 2 and 3 (1.5-2.3%). The incidence of clinically significant anticipatory nausea (score of ≥3) was 4.8, 7.9, and 8.3% before cycles 1, 2, and 3, respectively, with adjusted odds ratio (OR), 3.95 (95% confidence interval (CI), 2.23-7.00; p < 0.001) for patients with clinically significant nausea in prior cycles, compared with none. The adjusted ORs for other anticipatory NV endpoints ranged from 4.54-4.74 for patients with prior CINV. The occurrence of clinically significant anxiety in the prior cycle also resulted in a significantly increased likelihood of anticipatory nausea. CONCLUSIONS: These findings highlight the importance of preventing CINV in cycle 1 to reduce anticipatory NV in subsequent cycles.

Baseline patient characteristics, incidence of CINV, and physician perception of CINV incidence following moderately and highly emetogenic chemotherapy in Asia Pacific countries.

PURPOSE: This paper describes the incidence of chemotherapy-induced nausea and vomiting (CINV) after highly or moderately emetogenic chemotherapy (HEC or MEC) for cancer in six Asia Pacific countries. METHODS: Sequential adult patients naïve to chemotherapy and scheduled to receive at least two cycles of single-day HEC or MEC were enrolled in this prospective observational study. Patients completed the Multinational Association of Supportive Care in Cancer (MASCC) Antiemesis Tool on post-chemotherapy days 2 and 6 to record acute-phase (first 24 h) and delayed-phase (days 2-5) CINV. RESULTS: There were 648 evaluable patients (318 HEC, 330 MEC) from Australia (n = 74), China (153), India (88), Singapore (57), South Korea (151), and Taiwan (125). Mean (SD) patient age was 56 (12) and 58% of patients were women; the most common primary cancers were breast (27%), lung (22%), and colon (20%). Overall in cycle 1, complete response (no emesis or rescue antiemetics) was recorded by 69% (95% confidence interval (CI), 66-73) of all evaluable patients, with country percentages ranging from 55 to 78% (p < 0.001). After HEC, no emesis was recorded by 75% and no nausea by 38% of patients. After MEC, 80% had no emesis and 50% no nausea. Acute-phase CINV was better controlled than delayed-phase CINV, and the control of nausea was the lowest of any CINV measure in all phases. In a CINV perception survey, physicians tended to overestimate emesis rate and underestimate nausea rate. CONCLUSIONS: CINV remains a substantial problem, and country-specific information about CINV can be useful in developing strategies to improve outcomes for patients undergoing chemotherapy.

DOES ONE SIZE FIT ALL? COST UTILITY ANALYSES OF ALTERNATIVE MAMMOGRAPHIC FOLLOW-UP SCHEDULES, BY RISK OF RECURRENCE.

OBJECTIVES: International guidelines recommend annual mammography after early breast cancer, but there is no randomized controlled trial evidence to support this schedule over any other. Given that not all women have the same risk of recurrence, it is possible that, by defining different risk profiles, we could tailor mammographic schedules that are more effective and efficient. METHODS: A discrete event simulation model was developed to describe the progression of early breast cancer after completion of primary treatment. Retrospective data for 1,100 postmenopausal women diagnosed with early breast cancer in South Australia from 2000 to 2008 were used to calibrate the model. Women were divided into four prognostic subgroups based on the Nottingham Prognostic Index of their primary tumor. For each subgroup, we compared the cost-effectiveness of three different mammographic schedules for two different age groups. RESULTS: Annual mammographic follow-up was not cost-effective for most postmenopausal women. Two yearly mammography was cost-effective for all women with excellent prognosis tumors; and for women with good prognosis tumors if high compliance rates can be achieved. Annual mammography for 5 years and 2 yearly surveillance thereafter (a mixed schedule) may be cost-effective for 50- to 69-year-old women with moderate prognosis tumors, and for women aged 70-79 years with poor prognosis tumors. For younger women with poor prognosis tumors, annual mammography is potentially cost-effective. CONCLUSIONS: Our results suggest that mammographic follow-up could be tailored according to risk of recurrence. If validated with larger datasets, this could potentially set the stage for personalized mammographic follow-up after breast cancer.

MASCC/ISOO clinical practice guidelines for the management of mucositis secondary to cancer therapy.

BACKGROUND: Mucositis is a highly significant, and sometimes dose-limiting, toxicity of cancer therapy. The goal of this systematic review was to update the Multinational Association of Supportive Care in Cancer and International Society of Oral Oncology (MASCC/ISOO) Clinical Practice Guidelines for mucositis. METHODS: A literature search was conducted to identify eligible published articles, based on predefined inclusion/exclusion criteria. Each article was independently reviewed by 2 reviewers. Studies were rated according to the presence of major and minor flaws as per previously published criteria. The body of evidence for each intervention, in each treatment setting, was assigned a level of evidence, based on previously published criteria. Guidelines were developed based on the level of evidence, with 3 possible guideline determinations: recommendation, suggestion, or no guideline possible. RESULTS: The literature search identified 8279 papers, 1032 of which were retrieved for detailed evaluation based on titles and abstracts. Of these, 570 qualified for final inclusion in the systematic reviews. Sixteen new guidelines were developed for or against the use of various interventions in specific treatment settings. In total, the MASCC/ISOO Mucositis Guidelines now include 32 guidelines: 22 for oral mucositis and 10 for gastrointestinal mucositis. This article describes these updated guidelines. CONCLUSIONS: The updated MASCC/ISOO Clinical Practice Guidelines for mucositis will help clinicians provide evidence-based management of mucositis secondary to cancer therapy.

Predictors of acute adverse events from rapid rituximab infusion.

PURPOSE: This study aimed to identify the predictors of acute adverse events resulting from rapid rituximab infusion over 90 min. METHOD: It was a retrospective cohort study using medical record review based on a convenience sampling from 2007 till May 2011 in both in-patient and ambulatory setting in Royal Adelaide Hospital. RESULTS: There were a total of 294 patients who received 376 courses and 1,571 cycles of rapid rituximab infusion. Forty-three (14.6 %) patients experienced acute adverse events of hypotension being the most commonly occurring events followed by patients feeling hot and face-flushed. There were 11 predictors analysed, namely age, gender, diagnosis, stage of disease, presence of cardiac or lung morbidities, type of treatment, number of course and cycles, total white blood cells count, lymphocyte counts and lactate dehydrogenase using log generalised estimating equation for univariate and multivariate analysis. The findings successfully demonstrated that high lymphocyte counts were the independent predictor of acute adverse event from rapid rituximab infusion (p = 0.0009). Patient with high lymphocyte counts were 6.9382 times the odd to experience an adverse event as compared to those with normal lymphocyte counts. CONCLUSION: There are no specific patient characteristics to preclude prescribing rapid rituximab infusion following a 90-min regimen for non-Hodgkin lymphoma except a potential for adverse events to occur when patients have abnormally high lymphocyte counts.

Biomarkers of chemotherapy-induced diarrhoea: a clinical study of intestinal microbiome alterations, inflammation and circulating matrix metalloproteinases.

PURPOSE: A common side effect of chemotherapy treatment is diarrhoea. Unfortunately, the underlying mechanisms of chemotherapy-induced diarrhoea (CD) are poorly understood. We aimed to determine if faecal microbes of CD patients were displaced, if faecal calprotectin increased during CD and if there were alterations in circulating matrix metalloproteinases, nuclear factor kappa B (NF-κB), IL-1ß and TNF. PATIENTS AND METHODS: Twenty-six cancer patients receiving chemotherapy were enrolled and requested to provide stool samples and blood samples at various times during their chemotherapy cycle. Stool samples were analysed using conventional culture techniques and qRT-PCR. ELISA kits determined faecal calprotectin levels, levels of circulating matrix metalloproteinases and circulating NF-κB, IL-1ß and TNF. RESULTS: The majority of patients with CD showed decreases in Lactobacillus spp., Bifidobacterium spp., Bacteroides spp. and Enterococcus spp. Increases were observed in Escherichia coli and Staphylococcus spp. Methanogenic archaea were also quantified, with all patients except one showing a decrease. Faecal calprotectin levels were increased in 81.25 % of patients with CD. Circulating MMP-3 and MMP-9 significantly increased following chemotherapy. Circulating levels of NF-κB, IL-1ß and TNF were increased following chemotherapy, although this did not reach significance. CONCLUSIONS: We demonstrated that CD is associated with marked changes in intestinal microflora, methanogenic archaea, matrix metalloproteinase and serum levels of NF-κB, IL-1ß and TNF. These changes may result in diminished bacterial functions within the gut, altering gut function and initiating intestinal damage, resulting in the onset of diarrhoea. More importantly, these changes may provide clinicians with a possible new target for biomarkers of toxicity.

Systematic review of agents for the management of gastrointestinal mucositis in cancer patients.

PURPOSE: The aim of this study was to review the available literature and define clinical practice guidelines for the use of agents for the prevention and treatment of gastrointestinal mucositis. METHODS: A systematic review was conducted by the Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO). The body of evidence for each intervention, in each cancer treatment setting, was assigned an evidence level. Based on the evidence level, one of the following three guideline determinations was possible: recommendation, suggestion, and no guideline possible. RESULTS: A total of 251 clinical studies across 29 interventions were examined. Panel members were able to make one new evidence-based negative recommendation; two new evidence-based suggestions, and one evidence-based change from previous guidelines. Firstly, the panel recommends against the use of misoprostol suppositories for the prevention of acute radiation-induced proctitis. Secondly, the panel suggests probiotic treatment containing Lactobacillus spp., may be beneficial for prevention of chemotherapy and radiotherapy-induced diarrhea in patients with malignancies of the pelvic region. Thirdly, the panel suggests the use of hyperbaric oxygen as an effective means in treating radiation-induced proctitis. Finally, new evidence has emerged which is in conflict with our previous guideline surrounding the use of systemic glutamine, meaning that the panel is unable to form a guideline. No guideline was possible for any other agent, due to inadequate and/or conflicting evidence. CONCLUSIONS: This updated review of the literature has allowed new recommendations and suggestions for clinical practice to be reached. This highlights the importance of regular updates.

Advanced statistics identification of participant and treatment predictors associated with severe adverse effects induced by fluoropyrimidine-based chemotherapy.

PURPOSE: Adverse effects following fluoropyrimidine-based chemotherapy regimens are common. However, there are no current accepted diagnostic markers for prediction prior to treatment, and the underlying mechanisms remain unclear. This study aimed to determine genetic and non-genetic predictors of adverse effects. METHODS: Genomic DNA was analyzed for 25 single nucleotide polymorphisms (SNPs). Demographics, comorbidities, cancer and fluoropyrimidine-based chemotherapy regimen types, and adverse effect data were obtained from clinical records for 155 Australian White participants. Associations were determined by bivariate analysis, logistic regression modeling and Bayesian network analysis. RESULTS: Twelve different adverse effects were observed in the participants, the most common severe adverse effect was diarrhea (12.9%). Bivariate analysis revealed associations between all adverse effects except neutropenia, between genetic and non-genetic predictors, and between 8 genetic and 12 non-genetic predictors with more than 1 adverse effect. Logistic regression modeling of adverse effects revealed a greater/sole role for six genetic predictors in overall gastrointestinal toxicity, nausea and/or vomiting, constipation, and neutropenia, and for nine non-genetic predictors in diarrhea, mucositis, neuropathy, generalized pain, hand-foot syndrome, skin toxicity, cardiotoxicity and fatigue. The Bayesian network analysis revealed less directly associated predictors (one genetic and six non-genetic) with adverse effects and confirmed associations between six adverse effects, eight genetic predictors and nine non-genetic predictors. CONCLUSION: This study is the first to link both genetic and non-genetic predictors with adverse effects following fluoropyrimidine-based chemotherapy. Collectively, we report a wealth of information that warrants further investigation to elucidate the clinical significance, especially associations with genetic predictors and adverse effects.