Tag: General Medical Oncology & Hematology

SUMMARY: Bones are the third most common site of metastatic disease and approximately 100,000 cases of bone metastasis are reported in the United States each year. Cancers originating in the breast, prostate, lung, thyroid and kidney, are more likely to metastasize to the bone. Bisphosphonates inhibit osteoclast-mediated bone resorption and both oral and IV bisphosphonates reduce the risk of developing Skeletal Related Events (SRE’s) and delay the time to SRE’s in patients with bone metastases. Bisphosphonates can also reduce bone pain and may improve Quality of life. Intravenous bisphosphonates, Pamidronate (AREDIA®) and Zoledronic acid (ZOMETA®) have been approved in the US for the treatment of bone metastases. ZOMETA®, a third generation amino-bisphosphonate, has however largely replaced AREDIA® because of its superior efficacy, reducing pain and the incidence of Skeletal Related Events, by 25% to 40%. Both AREDIA® and ZOMETA® are administered IV every 3 to 4 weeks, following diagnoses of bone metastases. However, the optimal treatment schedule has remained unclear. Further, renal toxicity, long bone fractures and OsteoNecrosis of the Jaw (ONJ) have been identified as potential toxicities and the incidence of these toxicities increase with cumulative drug exposure.

The purpose of this study was to determine whether ZOMETA® administered every 12 weeks was non-inferior to ZOMETA® administered every 4 weeks. In this open-label, non-inferiority trial, 1822 patients were enrolled (Breast,N=855, Prostate,N=689 and Myeloma,N=278), and were randomly assigned in a 1:1 ratio to receive ZOMETA® every 4 weeks or every 12 weeks, for 2 years. The median age was 65 yrs and patients had at least one site of bone involvement. The Primary endpoint was incidence of at least one Skeletal Related Event within 2 years (defined as clinical fracture, spinal cord compression, radiation to bone, or surgery involving bone) after randomization. Secondary endpoints included skeletal morbidity rates (mean number of Skeletal Related Events per year), performance status, pain using the Brief Pain Inventory and incidences of ONJ and renal dysfunction. Both treatment groups were well matched. Patients in this trial were stratified by disease and analyses by disease, was pre-planned.

In the 795 patients who completed the study at 2 years, 29.5% of patients receiving ZOMETA® every 4 weeks and 28.6% of patients receiving ZOMETA® every 12 weeks experienced at least 1 Skeletal Related Event and this was not significantly different. With regards to Secondary endpoints, there were still no significant differences between the two treatment groups with regards to Pain scores, performance status scores, incidence of jaw osteonecrosis, and kidney dysfunction.

The authors concluded that ZOMETA® administered every 3 months for 2 years is non-inferior to ZOMETA®administered every 4 weeks for 2 years, among patients with breast cancer, prostate cancer and multiple myeloma, with bone metastases. A less frequent dosing of ZOMETA® compared with the standard monthly dosing, may also be more convenient for the patients and cost effective. XGEVA®, a RANK ligand (RANKL) inhibitor is also approved in the US for the treatment of bone metastases from solid tumors. A study is underway comparing XGEVA® administered every 4 weeks to every 12 weeks, in patients with metastatic breast and prostate cancer. Effect of Longer-Interval vs Standard Dosing of Zoledronic Acid on Skeletal Events in Patients With Bone Metastases. A Randomized Clinical Trial. Himelstein AL, Foster JC, Khatcheressian JL, et al. JAMA. 2017;317:48-58

SUMMARY: VISTOGARD® (Uridine Triacetate) is presently approved in the US for the emergency treatment of adult and pediatric patients, who had severe or life-threatening toxicities within 4 days of treatment, following an overdose of 5-FluoroUracil (5-FU) or XELODA® (Capecitabine). Toxicities related to 5-FU or XELODA® can be caused by impaired drug clearance, Dihydropyrimidine Dehydrogenase deficiency, and other genetic variations in the enzymes that metabolize 5-FU. Additionally, 5-FU overdoses resulting in death can occur because of infusion pump errors, dosage miscalculations and accidental or suicidal ingestion of XELODA®. These toxicities can manifest as severe mucositis, cytopenias, central neurotoxicity and acute cardiomyopathy.

VISTOGARD® is a pyrimidine analog and following oral administration is deacetylated by nonspecific esterases, yielding Uridine in the circulation. Uridine is a direct antagonist of 5-FU and competitively inhibits 5-FU from incorporating in normal tissues, thus reducing cell damage and cell death. The authors reported the efficacy of VISTOGARD® in two open-label clinical trials in which patients who presented with a 5-FU/XELODA® overdose (N=142) or patients with early onset of severe toxicities (N=26), were treated. These patients received VISTOGARD® granules 10 grams every 6 hours for 20 doses, starting within 96 hours after the termination of 5-FU/XELODA® therapy. The median age was 58 years. Because there were no antidotes available for 5-FU toxicity at the time of this study, and the use of a placebo was unethical, the outcomes of this study were compared to a historical cohort of patients gathered from all available literature (control group), who overdosed on 5-FU and received only best supportive care. The primary endpoint of these studies was survival at 30 days or until chemotherapy could resume, if prior to 30 days.

Of the 142 overdose patients treated with VISTOGARD®,137 patients (96%) survived and had a rapid reversal of severe acute cardiotoxicity and neurotoxicity and additionally, mucositis and leukopenia were prevented, or the patients recovered from them. In the historical control cohort, 21 of 25 patients (84%) died. Among the 141 VISTOGARD® treated overdose patients with a diagnosis of cancer, 53 resumed chemotherapy in less than 30 days (median time after 5-FU of 19.6 days), indicating a rapid recovery from toxicity. The most common toxicities in patients receiving VISTOGARD® included, nausea, vomiting and diarrhea.

The authors concluded that VISTOGARD® is a safe and effective antidote for 5-FU overexposure, and can facilitate rapid recovery and resumption of chemotherapy. Patients should take VISTOGARD® as soon as possible after overdose, regardless of symptoms or within 4 days of severe or life threatening toxicity. It should be noted that VISTOGARD® is not recommended for treatment of non-emergency adverse events associated with 5-FU and XELODA®, as this therapy may significantly decrease the efficacy of these chemotherapy agents. Emergency use of uridine triacetate for the prevention and treatment of life-threatening 5-fluorouracil and capecitabine toxicity. Ma WW, Saif WM, El-Rayes BF, et al. Cancer 2017;123:345-356.

SUMMARY: The FDA on August 10, 2016 approved SUSTOL® (Granisetron) extended- release injection, for use in combination with other antiemetics in adults, for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of Moderately Emetogenic Chemotherapy (MEC) or Anthracycline and Cyclophosphamide (AC) combination chemotherapy regimen. Chemotherapy Induced Nausea and Vomiting (CINV) is one of the most common adverse effects of chemotherapy and is experienced by about 80% of patients receiving chemotherapy. Acute CINV begins within the first 24 hours following chemotherapy administration, with most patients experiencing symptoms within the first four hours of treatment, whereas delayed nausea and vomiting occurs more than 24 hours after chemotherapy administration and can persist for several days. Delayed CINV is often underestimated and a third of the patients receiving chemotherapy may experience delayed nausea and vomiting without prior acute nausea or vomiting. Acute nausea and vomiting is dependent on Serotonin (5-hydroxytryptamine-5HT3) and its receptors, with the chemotherapeutic agents stimulating the release of Serotonin from the enterochromaffin cells of the small intestine. 5-HT3 receptors are located on vagal afferent pathway, which in turn activates the vomiting center to initiate the vomiting reflex. 5-HT3 receptors are also located centrally in the Chemoreceptor Trigger Zone of the area Postrema. Delayed nausea and vomiting is associated with the activation of Neurokinin 1 (NK1) receptors by substance P. NK1 receptors are broadly distributed in the central and peripheral nervous systems.

Granisetron is a first-generation serotonin-3 (5-HT3) receptor antagonist commonly used to treat CINV, but has a short half-life of approximately 8 hours. SUSTOL® is a novel formulation of 2 % Granisetron and a bioerodible tri(ethylene glycol) polymer, designed to provide slow, controlled hydrolysis, resulting in slow and sustained release of Granisetron, thereby preventing both acute and delayed CINV associated with MEC and Highly Emetogenic Chemotherapy (HEC). With a plasma half-life of 24-34 hours, this novel preparation formulation can maintain therapeutic levels of Granisetron for 5 or more days.

The FDA approval of SUSTOL® was based on the efficacy data from a multicenter double-blind trial which included 733 patients who received MEC or AC combination chemotherapy. Patients were randomized to receive either SUSTOL® 10 mg Subcutaneous injection (N=371) or ALOXI® 0.25 mg IV (N=362). This study was structured to compared SUSTOL® with ALOXI® (Palonosetron), which is also a serotonin-3 (5-HT3) receptor antagonist because, ALOXI® is not approved by the FDA to prevent delayed-onset CINV in patients who receive HEC. The trial was designed to allow for the evaluation of non-inferiority of SUSTOL® to ALOXI® in the acute and delayed phases. Antiemetics were administered 30 minutes before chemotherapy on Day 1. Dexamethasone was also administered IV at 8 or 20 mg on Day 1, depending on the chemotherapy regimen administered and those who received Dexamethasone 20 mg IV, were also given an 8 mg oral dose of the drug twice daily on Days 2, 3, and 4. The mean age was 57 years and 79% the patients were female. Approximately 55% of the patients received MEC regimen and 45% of the patients received AC combination chemotherapy. The most frequently used MEC regimen was Carboplatin and Paclitaxel combination (31%). The primary endpoint of the study was Complete Response (CR), which was defined as no emetic episodes or rescue medication during the acute phase (0-24 hours) and the delayed phase (more than 24 to 120 hours) after chemotherapy administration in cycle 1.

The results demonstrated that SUSTOL® was noninferior to ALOXI® . It was noted that among patients receiving MEC (N=406) the CR rate in the acute phase was 83% in the SUSTOL® group compared with 89% in the ALOXI® group. The CR rates in the delayed phase were 69% and 70% respectively. For those patients who received AC chemotherapy (N=327), the CR rate in the acute phase for the SUSTOL® group was 70% compared with 64% in the ALOXI® group. The CR rates in the delayed phase were 50% and 47% respectively. The safety of the FDA recommended dose of SUSTOL® (10 mg Subcutaneous dose), was evaluated in 924 patients across two double-blind, randomized active-controlled studies and it was noted that SUSTOL® was associated with a higher incidence of injection site reactions and constipation.

The authors concluded that SUSTOL® by virtue of its Biochronomer polymer-based drug delivery technology, represents a novel and convenient alternative to intravenous ALOXI® for the prevention of acute and delayed Chemotherapy Induced Nausea and Vomiting. Randomized phase III trial of APF530 versus palonosetron in the prevention of chemotherapy-induced nausea and vomiting in a subset of patients with breast cancer receiving moderately or highly emetogenic chemotherapy. Boccia R, O’Boyle E, Cooper W. BMC Cancer. 2016;16:166. doi:10.1186/s12885-016-2186-4.

SUMMARY: Chemotherapy Induced Nausea and Vomiting (CINV) is one of the most common adverse effects of chemotherapy and is experienced by about 80% of patients receiving chemotherapy. The development of effective antiemetic agents has facilitated the administration of majority of the chemotherapy agents in an outpatient setting avoiding hospitalization. Acute CINV begins within the first 24 hours following chemotherapy administration, with most patients experiencing symptoms within the first four hours of treatment, whereas delayed nausea and vomiting occurs more than 24 hours after chemotherapy administration and can persist for several days. Delayed CINV is often underestimated and a third of the patients receiving chemotherapy may experience delayed nausea and vomiting without prior acute nausea or vomiting. Acute nausea and vomiting is dependent on Serotonin (5-hydroxytryptamine-5HT3) and its receptors, with the chemotherapeutic agents stimulating the release of Serotonin from the enterochromaffin cells of the small intestine. 5-HT3 receptors are located on vagal afferent pathway, which in turn activates the vomiting center to initiate the vomiting reflex. 5-HT3 receptors are also located centrally in the Chemoreceptor Trigger Zone of the area Postrema. Delayed nausea and vomiting is associated with the activation of Neurokinin 1 (NK1) receptors by substance P. NK1 receptors are broadly distributed in the central and peripheral nervous systems.

ZYPREXA® (Olanzapine) is an antipsychotic agent that has been shown to block multiple neurotransmitters including Dopamine at D1, D2, D3, and D4 receptors, Serotonin at 5-HT2, 5-HT3 receptors, as well as Catecholamines at alpha1-adrenergic receptors, Acetylcholine at muscarinic receptors and Histamine at H1 receptors in the central nervous system. By virtue of its mechanism of action, ZYPREXA® might have significant antiemetic properties. Based on its pharmacological properties, this study evaluated the efficacy of ZYPREXA® for the prevention of nausea and vomiting, in patients receiving highly emetogenic chemotherapy.

The authors conducted a randomized, double-blind, phase III trial in which patients receiving ZYPREXA® (N=192) were compared to patients receiving Placebo (N=188). Patients received either ZYPREXA® 10 mg PO or matching Placebo daily, on days 1-4 of chemotherapy cycles. All patients additionally received Dexamethasone, Aprepitant or Fosaprepitant, and a 5-HT3 receptor antagonist. Eligible patients had no previous chemotherapy and were receiving Cisplatin at or more than 70 mg/m2 or Cyclophosphamide and Doxorubicin combination. The primary endpoint was nausea prevention and a Complete Response defined as no emesis and no use of rescue medication, was the secondary endpoint.

It was noted that the proportion of patients with no chemotherapy induced nausea was significantly greater with ZYPREXA® than with placebo in the first 24 hours after chemotherapy (74% versus. 45%, P=0.002), the time interval from 25 to 120 hours after chemotherapy (42% versus 25%, P=0.002) and across the overall 120-hour period (37% versus 22%, P=0.002). The Complete Response Rate was also significantly increased with ZYPREXA® during the three periods: 86% versus 65% (P<0.001), 67% versus 52% (P=0.007), and 64% versus 41% (P<0.001), respectively. Sedation, which is a side effect of ZYPREXA®, was observed on day 2 of treatment, with severe sedation noted in 5% of the patients.

The authors concluded that ZYPREXA® significantly improved nausea prevention, as well as Complete Response rate when compared to placebo, among previously untreated patients receiving highly emetogenic chemotherapy. Olanzapine for the Prevention of Chemotherapy-Induced Nausea and Vomiting. Navari RM, Qin R, Ruddy KJ, et al. N Engl J Med 2016; 375:134-142

SUMMARY: The American Cancer Society estimates that in 2016, 1,685,210 new cancer cases will be diagnosed in the United States and 595,690 cancer deaths are projected. It is a well established fact that physical activity reduces the risk of heart disease and all-cause mortality. Additionally, previously published studies have shown reduced risks for Colon, Breast and Endometrial cancers with physical activity. However, it has remained unclear whether physical activity reduces risk of other cancers, which together constitute approximately 75% of all cancers in the United States.

It has been hypothesized that the link between physical activity and cancer is mediated through both hormonal as well as non-hormonal pathways. Hormonal systems such as sex steroids, insulin and insulin-like growth factors, and adipokines can initiate cancer cell growth. Intervention with physical activity by partly reducing adiposity, decreases the levels of estrone, estradiol and insulin in postmenopausal women. Non-hormonal mechanisms linking physical activity to cancer risk, include inflammation, immune function, oxidative stress, and for colon cancer, a reduction in transit time for waste to pass through the gastrointestinal tract.

The authors in this study examined pooled data from 12 prospective cohort studies involving 1.44 million participants, to find out whether there was an association of leisure-time physical activity with incidence of 26 different cancer types. They also examined whether these associations were evident regardless of body size or smoking history. Leisure-time physical activities were defined as activities done at an individual’s discretion, to improve or maintain fitness or health. This could include walking, running, swimming or other moderate- to vigorous-intensity activities. The median physical activity in this study was equivalent to 150 minutes of moderate-intensity activity every week and comparable to the current recommended minimum physical activity level for the US population. Leisure-time physical activity was assessed by self-reported surveys. The median age was 59 years and median BMI was 26.

Participants were followed for a median of 11 years during which period 187,000 new cases of cancer occurred. The authors noted that leisure-time physical activity was associated with lower risk of 13 of 26 cancer types which included Esophageal adenocarcinoma, Liver, Lung, Kidney, Gastric cardia, Endometrial, Myeloid Leukemia, Myeloma, Colon, Head and Neck, Rectal, Bladder and Breast. The greatest risk reduction was noted for Esophageal adenocarcinoma. These associations were evident regardless of body size or smoking history in most cases.

The authors concluded that leisure-time physical activity not only reduces risk of heart disease and risk of death from all causes, but also lowers risk of many types of cancer, regardless of body size or smoking history. Physical activity should therefore be promoted for population-wide cancer prevention and control. Association of Leisure-Time Physical Activity With Risk of 26 Types of Cancer in 1.44 Million Adults. Moore SC, Lee I, Weiderpass E, et al. JAMA Intern Med. 2016;176:816-825.

SUMMARY: The American Cancer Society released the Cancer Statistics 2016 report, which includes the most recent data on cancer incidence, mortality, and survival in the US. It is estimated that in 2016, 1,685,210 new cancer cases will be diagnosed in the US and 595,690 cancer deaths are projected.

With a considerable decline in mortality from heart disease, cancer is now the leading cause of death in 21 states. In males, prostate cancer will be the leading cancer diagnosis in 2016 (21%) and Breast Cancer will be the leading cancer diagnosis in women (29%).

Lung Cancer remains the leading cause of cancer death both in men and women (27%). With major therapeutic advances against leukemia, brain cancer is now the leading cause of cancer death among children and adolescents (birth-19 years).

The overall cancer incidence rate in women has remained stable since 1998. However in men, cancer incidence has decreased by 3.1% per year since 2009 and this has been attributed to decline in routine screening with the PSA test. Routine screening with the PSA test is no longer recommended because of high rates of overdiagnosis, estimated at 23% to 42% for screen-detected cancers, which may not result in bad outcomes.

The cancer death rate in the US has dropped by 23% since 1991 which translates to more than 1.7 million deaths averted through 2012. There has been a continued decrease in death rates for the four major cancer sites – lung, breast, prostate, and colon/rectum. This overall decline in cancer deaths may be the result of reduction in smoking prevalence, improved screening modalities for breast, colon and prostate cancers and improvements in treatment.

Despite the overall reduction in cancer mortality, death rates are increasing for cancers of the liver, pancreas, and uterine corpus. Obesity has been shown to increase endometrial cancer risk by 50% for every 5 body mass index (BMI) units. Chronic infection with Helicobacter pylori and Hepatitis B virus has increased the incidence and death rates of stomach and liver cancer, respectively.

The authors concluded that “Advancing the fight against cancer will require continued clinical and basic research, which is dependent on funding, as well as the application of existing cancer control knowledge across all segments of the population, with an emphasis on disadvantaged groups.” With progress being made in cancer prevention using improved screening techniques and behavioral interventions, as well as rapid advances in cancer treatment with the understanding of cancer biology, it is expected that cancer death rate will continue to decline in the years to come. Cancer statistics, 2016. Siegel RL, Miller KD and Jemal A. CA Cancer J Clin 2016;66:7-30.

SUMMARY: The United States FDA approved VISTOGARD® (Uridine Triacetate) for the emergency treatment of adult and pediatric patients, who had severe or life-threatening toxicities within 4 days of treatment, following an overdose of 5-FluoroUracil (5-FU) or XELODA® (Capecitabine). VISTOGARD® is a Pyrimidine analog and following oral administration is deacetylated by nonspecific esterases, yielding Uridine in the circulation. Uridine is a direct antagonist of 5-FU and competitively inhibits 5-FU from incorporating in normal tissues, thus reducing cell damage and cell death.

The approval of VISTOGARD® was based on two separate trials in which 135 adult and pediatric cancer patients at increased risk for toxicity with 5-FU or XELODA® were included. Risk for toxicity could be due to 5-FU overdose and accidental XELODA® ingestion (N=111) or DihydroPyrimidine Dehydrogenase (DPD) deficiency and/or patients who experienced rapid onset of severe toxicities (N=24). These patients received VISTOGARD® granules 10 grams every 6 hours for 20 doses, starting within 96 hours after the termination of 5-FU therapy. The primary endpoint of the studies was survival at 30 days or until chemotherapy could resume, if prior to 30 days.

Of those who were treated with VISTOGARD® for overdose, 97 percent were still alive at 30 days. Of those treated with VISTOGARD® for early-onset severe or life-threatening toxicity, 89 percent were alive at 30 days. In both studies, 33 percent of patients resumed chemotherapy in less than 30 days. Adverse events were mild and uncommon and included nausea, vomiting and diarrhea.

The authors concluded that VISTOGARD® is a safe and effective antidote for 5-FU overexposure, and can facilitate rapid recovery and resumption of chemotherapy. Patients should take VISTOGARD® as soon as possible after overdose, regardless of symptoms or within 4 days of severe or life threatening toxicity. It should be noted that VISTOGARD® is not recommended for treatment of non-emergency adverse events associated with 5-FU and XELODA®, as this therapy may significantly decrease the efficacy of these chemotherapy agents. Clinical trial experience with uridine triacetate for 5-fluorouracil toxicity. Ma WW, Saif WM, El-Rayes BF, et al. J Clin Oncol 34, 2016 (suppl 4S; abstr 655)