Effect of Opioid Exposure on Efficacy and Tolerability of Sublingual Fentanyl and Subcutaneous Morphine for Severe Cancer Pain Episodes. Secondary Analysis From a Double-Blind Double-Dummy, Randomized Trial.

CONTEXT: Few studies have addressed the impact of previous opioid exposure on the effect of opioids for the treatment of severe cancer pain episodes. OBJECTIVES: We aimed to test whether previous exposure to higher opioid doses was associated with a reduced analgesic effect of fentanyl sublingual tablets (FST) and subcutaneous morphine (SCM) and whether it had an influence on their relative effect. METHODS: This is a secondary analysis of a placebo-controlled randomized trial comparing 100 µg FST with 5 mg SCM for the acute treatment of severe cancer pain episodes. The effect of previous opioid exposure (oral morphine equivalent daily dose from 20 to 120 mg) on pain intensity difference (PID) and side effects at 30 and 60 minutes after administration (PID 0-30 minutes, PID 0-60 minutes, and adverse events 30-60 minutes) and on re-medication for inefficacy, was studied by multivariable linear and logistic regression models and statistical tests for interaction. RESULTS: A total of 114 patients were enrolled. Results indicate modest and nonstatistically significant effect of previous opioid exposure on all the outcomes examined (P = 0.11, P = 0.35, P = 0.07, and P = 0.52, respectively, for PID 0-30 minutes, re-medication, PID 0-60 minutes, and adverse events 30-60 minutes). Nonstatistically significant tests for interaction for all models indicated a lack of impact of previous opioid exposure on the difference in the analgesic effect between treatments. CONCLUSION: In this study, we could not demonstrate an effect of previous opioid exposure, from 20 to 120 mg oral morphine equivalent daily dose, on the absolute and relative efficacy and tolerability of 100 µg FST and 5 mg SCM for severe cancer pain episodes.

Perioperative Triplet Chemotherapy and Cetuximab in Patients With RAS Wild Type High Recurrence Risk or Borderline Resectable Colorectal Cancer Liver Metastases.

BACKGROUND: For borderline resectable colorectal cancer liver metastases (CLM), systemic treatment can help to achieve R0 resection and reduce the risk of relapse. We assessed the role of perioperative triplet chemotherapy in combination with cetuximab in patients with RAS wild type high recurrence risk and/or borderline resectable CLM. PATIENTS AND METHODS: This was a monocenter, open-label phase II study. Borderline resectability was defined technically as tumor involvement of >1 hepatic vein, or >4 hepatic segments, need for 2-stage hepatectomy or radiofrequency ablation, and/or biologically (high risk): ≥4 metastatic nodules, or synchronous metastases. Patients were treated with 4 pre- and postoperative cycles of biweekly COI-E (cetuximab 500 mg/m2 and irinotecan 180 mg/m2 on day 1, oxaliplatin 85 mg/m2 on day 2, and capecitabine 1000 mg/m2 twice per day on days 2-6). The primary end point was overall response rate. RESULTS: Forty patients were enrolled. Nine patients with KRAS mutation were excluded after amendment in 2010. In an extended RAS test we did not find additional RAS mutations. The final population was comprised of 31 patients with RAS wild type CLM (technically borderline resectable 39%; synchronous 84%; ≥4 metastatic nodules 29%). The overall response, R0 resection, and pathological response rates were 87%, 84%, and 33%, respectively. At a median follow-up of 4 years, median progression-free survival and overall survival were 17.8 and 62.5 months, respectively. Treatment toxicity was relevant but did not jeopardize the surgical plan. CONCLUSION: The COI-E regimen was associated with high response and R0 resection rates in patients with RAS wild type CLM with borderline resectability and/or high-risk features.

Palonosetron in the prevention of chemotherapy-induced nausea and vomiting: an evidence-based review of safety, efficacy, and place in therapy.

INTRODUCTION: The second-generation 5-hydroxytryptamine-3 (5-HT3) receptor antagonist palonosetron is effective in the prevention of chemotherapy-induced nausea and vomiting (CINV) associated with highly and moderately emetogenic chemotherapy (HEC and MEC, respectively). In addition, palonosetron has been the first and, at present, the only 5-HT3 receptor antagonist to have a specific indication for the prevention of delayed CINV associated with MEC. The unique pharmacology of this antagonist is thought to partly explain its improved efficacy against delayed symptoms. AIMS: To review the evidence underlying the use of palonosetron in preventing CINV. EVIDENCE REVIEW: A recent meta-analysis consistently showed that palonosetron significantly increases the control of both emesis and nausea during the acute and delayed phases after single-day HEC or MEC. Consistent with these findings from trials that did not include an neurokinin-1 (NK-1) receptor antagonist, randomized controlled trials recently showed that a triple combination with palonosetron achieves significantly better control of delayed CINV, particularly delayed nausea, in patients undergoing HEC or the high-risk combination of an anthracycline and cyclophosphamide (AC). Evidence from randomized studies also supports palonosetron as a valuable option to reduce the total corticosteroid dose administered in patients undergoing multiple cycles of MEC or AC chemotherapy. Additional benefits of palonosetron include the lack of a warning on cardiac safety and no known clinically significant drug-drug interactions. Place in therapy and conclusion: Evidence currently available indicates that palonosetron significantly adds to the clinician's ability to effectively control CINV in patients undergoing HEC or MEC. It is recommended in the international guidelines for the prevention of CINV caused by MEC. The high safety profile and the opportunity to reduce the total corticosteroid dose with no loss in efficacy against delayed CINV should also contribute to a wider use of palonosetron in clinical practice.

Undetected toxicity risk in pharmacogenetic testing for dihydropyrimidine dehydrogenase.

Fluoropyrimidines, the mainstay agents for the treatment of colorectal cancer, alone or as a part of combination therapies, cause severe adverse reactions in about 10%-30% of patients. Dihydropyrimidine dehydrogenase (DPD), a key enzyme in the catabolism of 5-fluorouracil, has been intensively investigated in relation to fluoropyrimidine toxicity, and several DPD gene (DPYD) polymorphisms are associated with decreased enzyme activity and increased risk of fluoropyrimidine-related toxicity. In patients carrying non-functional DPYD variants (c.1905+1G>A, c.1679T>G, c.2846A>T), fluoropyrimidines should be avoided or reduced according to the patients' homozygous or heterozygous status, respectively. For other common DPYD variants (c.496A>G, c.1129-5923C>G, c.1896T>C), conflicting data are reported and their use in clinical practice still needs to be validated. The high frequency of DPYD polymorphism and the lack of large prospective trials may explain differences in studies' results. The epigenetic regulation of DPD expression has been recently investigated to explain the variable activity of the enzyme. DPYD promoter methylation and its regulation by microRNAs may affect the toxicity risk of fluoropyrimidines. The studies we reviewed indicate that pharmacogenetic testing is promising to direct personalised dosing of fluoropyrimidines, although further investigations are needed to establish the role of DPD in severe toxicity in patients treated for colorectal cancer.

Bevacizumab treatment in the elderly patient with metastatic colorectal cancer.

Metastatic colorectal cancer (mCRC), like many cancers, is primarily a disease of elderly people. Despite this prevalence, such patients are often excluded from randomized trials or represent a minority of enrolled patients. Moreover, the criteria for establishing benefit or side effects of treatment strategies in this population are uncertain and not well recognized. Bevacizumab improves the outcome of mCRC when used in combination with standard first-line and second-line chemotherapy and beyond the first disease progression when given with a chemotherapy backbone different from that used in the precedent line. The particular toxicity profile of this antiangiogenesis agent (in particular hypertension, thromboembolic events, hemorrhage, and renal failure) may discourage its use in elderly patients with comorbidities. Data from subgroup analyses of randomized trials and the results of recent cohort studies suggest a significant benefit from the addition of bevacizumab to standard chemotherapy for elderly patients comparable with that observed in younger patients, except for the increased risk for thromboembolic events. Age alone should not be a barrier to use of bevacizumab, and further research with a more complete geriatric assessment should investigate the role of bevacizumab in elderly patients with mCRC to avoid undertreatment of this patient population due to a historical conservative approach.

Chemotherapy or targeted therapy as second-line treatment of advanced gastric cancer. A systematic review and meta-analysis of published studies.

Chemotherapy is a cornerstone in treatments of gastric cancer, but despite its benefit, less than 60% of patients receive salvage therapy in clinical practice. We performed a systematic review and meta-analysis based on trial data on the role of second-line treatment of advanced gastric cancer. MEDLINE/PubMed and Cochrane Library were searched for randomized phase III trials that compared active therapy to best supportive care in advanced gastric cancer. Data extraction was conducted according to the PRISMA statement. Summary HR for OS was calculated using a hierarchical Bayesian model and subgroup analysis was performed based on baseline Eastern Cooperative Oncology Group Performance Status (ECOG) performance status (0 vs. 1 or more). A total of 1,407 patients were evaluable for efficacy, 908 were treated in the experimental arms, with chemotherapy (231 pts) or with targeted therapies (677 pts). The risk of death was decreased by 18% (HR = 0.82; 95% CI, 0.79-0.85; posterior probability HR≥1: <0.00001) with active therapies. Chemotherapy and ramucirumab were able to decrease this risk by 27% and 22%, respectively. No differences were found between chemotherapy and ramucirumab. In patients with ECOG = 0 a greater benefit was found for chemotherapy with a reduction of the risk of death by 43% and no benefits were found for ramucirumab or everolimus. In patients with ECOG = 1 or more a significant reduction of the risk of death by 32% was reported in patients treated with ramucirumab, even if no significant difference was reported between chemotherapy and ramucirumab. This analysis reports that active and available therapies are able to prolong survival in patients with advanced gastric cancer with a different outcome based on initial patient's performance status. New trials based on a better patient stratification are awaited.

Incidence and relative risk of grade 3 and 4 diarrhoea in patients treated with capecitabine or 5-fluorouracil: a meta-analysis of published trials.

AIM: Capecitabine is an oral fluoropyrimidine that can effectively replace infusional 5-fluorouracil (5-FU) for treatment of colorectal, gastric and breast cancer. This study aims to analyze the incidence and the relative risk of grade 3 and 4 diarrhoea in patients treated with capecitabine or 5-FU in randomized clinical trials (RCTs). METHODS: MEDLINE and Cochrane Library were reviewed for RCTs that compared capecitabine with 5-FU for treatment of solid malignancies. The incidence and relative risk (RR) of grade 3/4 diarrhoea were estimated for each arm in the overall population and in colorectal cancer (CRC) patients RESULTS: Twenty-three studies and 15,761 patients were included. Among these 8303 and 7458 patients received capecitabine or 5-FU based therapies, respectively. In the overall populations severe diarrhoea was reported in 16.6% (95% CI 15.8, 17.4) and in 12.7% (95% CI 11.9, 13.4) of patients treated with capecitabine or 5-FU-based therapies, respectively. The RR was 1.39 (95% CI 1.14, 1.69, P = 0.0010). In 14,899 CRC patients, the incidence of severe diarrhoea was 17.0% (95% CI 16.2, 17.9) and 12.9% (95% CI 12.1, 13.7), respectively, with a RR of 1.46 (95% CI 1.18, 1.81, P < 0.0001). In CRC patients treated with combined chemotherapy, the RR was 1.40 (95% CI 1.07, 1.82; P = 0.01) for patients receiving oxaliplatin and 2.35 (95% CI 1.76, 3.13; P < 0.0001) for patients receiving irinotecan. CONCLUSIONS: Treatment with capecitabine is characterized by an increased risk of severe diarrhoea, mainly in patients affected by CRC and treated with polichemotherapy. Combination treatment with irinotecan doubles the risk over 5-FU.

FOLFOX-4 chemotherapy for patients with unresectable or relapsed peritoneal pseudomyxoma.

PURPOSE: The standard treatment of peritoneal pseudomyxoma is based on cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC). The establishment of newer systemic treatments is an unmet clinical need for unresectable or relapsed peritoneal pseudomyxoma. The aim of our study was to assess the activity of chemotherapy with 5-fluorouracil and oxaliplatin (FOLFOX-4 regimen) in terms of response rate in this subset of patients. MATERIALS AND METHODS: Patients were included in a single-center, observational study and treated with FOLFOX-4 administered every 2 weeks for up to 12 cycles or until progressive disease or unacceptable toxicity. RESULTS: Twenty consecutive patients were reviewed from July 2011 to September 2013. Only partial responses were observed, with an objective response rate of 20%. Median progression-free survival and overall survival were 8 months and 26 months, respectively. Two patients were able to undergo laparotomy with complete cytoreduction and HIPEC in one case. Safety data for FOLFOX-4 were consistent with the literature. By means of a mutant enriched polymerase chain reaction, KRAS mutation was found in 16 of 19 cases (84%), and MGMT promoter methylation was found in 8 (42%, all KRAS mutant). CONCLUSION: FOLFOX-4 chemotherapy is tolerable and active in patients with peritoneal pseudomyxoma when disease is deemed unresectable or relapsed after peritonectomy and HIPEC. The identification of predictive biomarkers, such as KRAS for resistance to anti-epidermal growth factor receptor monoclonal antibodies and MGMT for response to temozolomide, is a priority for the development of evidence-based treatment strategies for peritoneal pseudomyxoma.

Palonosetron plus dexamethasone in highly emetogenic chemotherapy: pooled data from two Phase III trials.

AIM: Data from two randomized trials were pooled to further characterize the effectiveness of palonosetron combined with dexamethasone in the setting of highly emetogenic chemotherapy. PATIENTS & METHODS: The analysis included 1411 patients who were randomized to receive palonosetron or ondansetron/granisetron intravenously on day 1 plus either 1-day or 3-day dexamethasone dosing. The primary end point was complete response (no vomiting and no rescue antiemetics over days 1-5) in cycle one. Data across the studies were analyzed by the Mantel-Haenszel method. RESULTS: The vast majority of patients received either cisplatin (62%) or anthracycline plus cyclophosphamide (34%). The palonosetron regimen provided a 12 percentage-point improvement in the rate of overall complete response compared with the control regimen (49.2 vs 37.3%; odds ratio: 1.65; 95% CI: 1.33-2.04; p < 0.0001). The frequency of no delayed nausea at all daily periods was consistently higher in the palonosetron group. CONCLUSION: The current analysis confirmed that palonosetron plus dexamethasone improved control of highly emetogenic chemotherapy-induced nausea and vomiting throughout 5 days postchemotherapy to a significantly greater extent than the combination including older 5-HT3 antagonists.

Is a dexamethasone-sparing strategy capable of preventing acute and delayed emesis caused by combined doxorubicin and paclitaxel for breast cancer? Analysis of a phase II trial.

OBJECTIVE: The effectiveness of palonosetron without delayed dexamethasone dosing against emesis was investigated in patients scheduled to receive the corticosteroid-containing combination of doxorubicin and paclitaxel (AT) for 3 cycles. METHODS: Chemo-naïve women with breast cancer receiving doxorubicin (60 mg/m(2)) and paclitaxel (200 mg/m(2)) were eligible. Patients received palonosetron 0.25 mg intravenously before chemotherapy, however, all patients also received a premedication consisting of prednisone (25 mg orally the evening before therapy) and hydrocortisone (250 mg intravenously just before paclitaxel). The primary end point was complete control (CC; no vomiting, no rescue anti-emetics, and no more than mild nausea) during the overall phase (days 1-5) following cycle 1. RESULTS: Seventy-six patients were enrolled and evaluable (median age 50 years). Fifty-six patients (74%; 95% CI 62-83%) achieved overall CC. Acute (day 1) and delayed (days 2-5) CC rates were 78 and 74%, respectively. No vomiting rates for the acute, delayed and overall phases were 85, 85 and 83%, respectively. An exploratory analysis showed only a small decrease in the probability of achieving CC between cycle 1 (74%) and cycle 3 (66%). CONCLUSION: The dexamethasone-sparing strategy prevented emesis in more than 70% of breast cancer patients receiving their initial cycle of AT chemotherapy.

Safety, efficacy, and patient acceptability of single-dose fosaprepitant regimen for the prevention of chemotherapy-induced nausea and vomiting.

Control of chemotherapy-induced nausea and vomiting (CINV) is a crucial factor in ensuring that patients undergoing cancer chemotherapy can get the full benefit of therapy. Current antiemetic guidelines recommend that the neurokinin-1 receptor (NK-1R) antagonist aprepitant should be used as part of a combination regimen with dexamethasone and a serotonin receptor antagonist for the prevention of CINV in patients receiving highly emetogenic chemotherapy (HEC). Fosaprepitant is a water-soluble N-phosphoryl derivative of aprepitant that, when infused, is rapidly metabolized back to an active aprepitant. The existing literature in PubMed about fosaprepitant was screened and selected in order to address the emerging data from two randomized clinical trials evaluating the efficacy and safety of a single-dose fosaprepitant regimen. These phase III trials demonstrated that fosaprepitant given as a single intravenous dose of 150 mg was either noninferior to the conventional 3-day aprepitant or significantly superior to placebo for the prevention of acute and delayed CINV in patients receiving high-dose cisplatin. In both trials, fosaprepitant was well tolerated although more frequent infusion-site adverse events were observed with fosaprepitant. The new dosage regimen of fosaprepitant, therefore, would be an option for CINV control in patients receiving cisplatin-based chemotherapy. The clinical efficacy is consistent with the findings from a time-on-target, positron-emission tomography study evaluating the NK-1R occupancy in the central nervous system (CNS) over 5 days after a single-dose infusion of 150 mg fosaprepitant in healthy participants. The single-dose regimen is capable of blocking more than 90% of the NK-1Rs in the CNS for at least 48 hours after infusion, which is sufficient to control delayed CINV for 2 to 5 days after HEC. The new dosage regimen of fosaprepitant can provide a simplified treatment option that maintains high protection while ensuring adherence to scheduled antiemetic medication throughout most of the 5-day period encompassing the major risk for CINV.

Lapatinib and letrozole as first-line therapy for metastatic breast cancer: case report of bone metastasis 18 years later.

We describe a 63-year-old woman with a diagnosis of breast cancer who relapsed with multiple bone lesions 18 years later. The biological characteristics were estrogen receptor positive, progesterone receptor positive, and HER2-positive cancer. Lapatinib and letrozole was the treatment of choice as a manageable and active first-line therapy for this patient.