Tag: General Medical Oncology & Hematology

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)

SUMMARY: Immunotherapy in cancer management includes Cancer Vaccines, Cytokine therapy, Adoptive Cell therapy and therapy with Check Point protein inhibitors such as YERVOY®, KEYTRUDA® and OPDIVO®. Toxicities related to these immunotherapeutic interventions are mediated by T cells resulting in exaggerated T cell response and potential damage to normal tissues. A brief summary of the more common adverse events associated with cancer immunotherapy, is listed below-

CANCER VACCINES

PROVENGE® (Sipuleucel-T) is an autologous, cellular immunotherapy indicated for the treatment of asymptomatic or minimally symptomatic metastatic Castrate Resistant (hormone-refractory) Prostate Cancer. This product is the only currently approved Cancer Vaccine and consists of autologous CD54+ cells activated with recombinant PAP/GM-CSF (Prostate Acid Phosphatase, an antigen expressed in the prostate cancer tissue, linked to immune cell activator, Granulocyte Macrophage-Colony Stimulating Factor). Vaccine therapies work by promoting type 1 or type 2 immune reactions. In type 1 immune reaction, T helper type 1 (Th1) lymphocytes secrete Interleukin-2 (IL-2), Interferon gamma, and lymphotoxin-alpha and facilitate intense phagocytic activity whereas in type 2 immunity, Th2 cells secrete IL-4, IL-5, IL-9, IL-10, and IL-13 and is characterized by high antibody titers. Cancer Vaccines are associated with minimal toxicities because the antigens associated with the tumor are overexpressed in the cancer cells and are not usually detectable in normal cells. Common side effects include local reactions, fever, chills, fatigue, rash, back pain and Melanoma vaccines are associated with vitiligo.

CYTOKINE THERAPY

Both INTRON® A (Interferon alfa-2b) and ROFERON® A (Interferon alfa-2a) are approved for a variety of malignant conditions as well as for Chronic Hepatitis B and C. In addition to fever, chills and flu like symptoms, two thirds of the patients have nausea and anorexia and up to 45% of the patients may experience symptoms of depression. Patients should be monitored for cytopenias, diarrhea, liver toxicities as well as thyroid dysfunction and autoimmune disorders may be exacerbated with Interferon.

PROLEUKIN® (High dose IL-2) is administered in an inpatient setting with cardiac monitoring, as patients often develop capillary leak syndrome and hypotension in addition to flu like symptoms and liver function abnormalities. This has been attributed to release of Nitric Oxide, IL-1, Tumor Necrosis Factor alpha, and IFN gamma. Patients may also develop autoimmune related thyroid dysfunction, cytopenias as well as neurotoxicity and will therefore require close monitoring.

ADOPTIVE CELL THERAPY

Unlike Cancer Vaccines, Adoptive T cell therapy is a type of passive immunization which involves the transfusion of autologous or allogeneic T cells into patients with malignancies. These tumor reactive T cells can be genetically engineered or grown ex vivo and their efficacy can be enhanced by other immunotherapies, such as Cancer Vaccines, Cytokine administration or in some instances cytotoxic chemotherapy and radiation therapy. BLINCYTO® (Blinatumomab) is a genetically engineered bispecific CD19 directed CD3 T-cell engager, approved by the FDA, that binds to CD19 (expressed on B-cells) and CD3 (expressed on T-cells). It is indicated for the treatment of Philadelphia chromosome-negative relapsed or refractory B-cell precursor Acute Lymphoblastic Leukemia (ALL). Administration of BLINCYTO® or high dose IL-2 given along with T cells, can cause Cytokine Release Syndrome (CRS), associated with fever, tachycardia, vascular leak, oliguria, and hypotension. This has been attributed to IL-6 and ACTEMRA® (Tocilizumab), an IL-6 receptor antagonist may be of benefit for these patients along with IV fluids, nonsteroidal anti-inflammatory agents and vasopressors. Other toxicities that require monitoring include flu like symptoms, liver function abnormalities, B-cell aplasia, cytopenias and neurotoxicity.

THERAPY WITH CHECKPOINT INHIBITORS

The FDA approved checkpoint inhibitors include, YERVOY® (Ipilimumab) which targets CTLA-4, KEYTRUDA® (Pembrolizumab) and OPDIVO® (Nivolumab), which block checkpoint PD-1. The toxicities associated with YERVOY® are dose dependant. Some common side effects of check point inhibitors include skin rash, flu like symptoms, liver function abnormalities, diarrhea and colitis, cytopenias, thyroid and adrenal function abnormalities. Rare cases of pneumonitis, encephalitis, Guillain-Barré syndrome, and a myasthenia gravis–like syndrome have been reported. With close monitoring, early diagnosis and intervention with Corticosteroids, these toxicities can be alleviated. REMICADE® (Infliximab), a chimeric monoclonal antibody against Tumor Necrosis Factor alpha (TNF-alpha), should be offered to those whose colitis does not resolve within 3 days of high dose steroids or for relapse of colitis with steroid taper.

Toxicities of Immunotherapy for the Practitioner. Weber JS, Yang JC, Atkins MB, et al. J Clin Oncol 2015;33:2092-2099

SUMMARY: The U.S. Food and Drug Administration on September 2, 2015, approved VARUBI® (Rolapitant) to prevent delayed phase Chemotherapy Induced Nausea and Vomiting (CINV). 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. VARUBI® is a substance P/Neurokinin-1 (NK-1) receptor antagonist.

The safety and efficacy of VARUBI® were established in three randomized, double-blind, controlled clinical trials where VARUBI® in combination with KYTRIL® (Granisetron) and Dexamethasone was compared with placebo, KYTRIL® and Dexamethasone (control therapy), in more than 2500 patients receiving a moderately or highly emetic chemotherapy regimen. HEC Study 1 and HEC Study 2 included Cisplatin Based Highly Emetogenic Chemotherapy (HEC). Chemotherapy regimens included more than 60 mg/m2 of Cisplatin. In HEC Study 1, 532 patients were randomized to receive either antiemetic regimen with VARUBI® (N =266) or control therapy (N =266). In HEC Study 2, a total of 555 patients were randomized to receive either antiemetic regimen with VARUBI® (N =278) or control therapy (N =277). MEC Study 3 included Moderately Emetogenic Chemotherapy and combinations of Anthracycline and Cyclophosphamide chemotherapy. A total of 1369 patients were randomized in this study to receive either antiemetic regimen with VARUBI® (N =684) or control therapy (N =685). Patients in these trials received either VARUBI® 180 mg PO or placebo at 1 to 2 hours before administration of Highly Emetogenic Chemotherapy. All patients received intravenous KYTRIL® 10 μg/kg IV and Dexamethasone 20 mg PO on day 1 and Dexamethasone 8 mg PO twice daily on days 2 to 4 for up to six cycles, with each cycle lasting a minimum of 14 days. The primary endpoint in all three studies was complete response (defined as no emetic episodes and no rescue medication) in the delayed phase (25 to 120 hours) post chemotherapy.

It was noted that a significantly greater proportion of patients receiving antiemetic regimen with VARUBI® had complete responses in the delayed phase than did patients in the control therapy group – HEC Study 1: 72.7% vs 58.4% (P<0.001), HEC Study 2: 70.1% vs 61.9% (P=0.043) and MEC Study 3: 71.3% vs 61.6% (P<0.001). The most common adverse events in patients treated with VARUBI® included neutropenia, hiccups, decreased appetite and dizziness. It was concluded from these three trials that VARUBI® when combined with a 5-HT3 receptor antagonist such as KYTRIL® and a corticosteroid, significantly prevented delayed Chemotherapy Induced Nausea and Vomiting.

1) Safety and efficacy of rolapitant for prevention of chemotherapy-induced nausea and vomiting after administration of cisplatin-based highly emetogenic chemotherapy in patients with cancer: two randomised, active-controlled, double-blind, phase 3 trials. Rapoport BL, Chasen MR, Gridelli C, et al. The Lancet Oncology 2015;16:1079-1089

2) Phase 3 trial results for rolapitant, a novel NK-1 receptor antagonist, in the prevention of chemotherapy-induced nausea and vomiting (CINV) in subjects receiving moderately emetogenic chemotherapy (MEC). Schnadig ID, Modiano MR, Poma A, et al. J Clin Oncol 32:5s, 2014 (suppl; abstr 9633)

SUMMARY: The Centers for Disease Control and Prevention (CDC) estimates that there are 800,000 -1.4 million individuals with Chronic Hepatitis B (HBV) infection in the United States. Reactivation of HBV is a major concern in cancer patients who may be on chemotherapy or other immunosuppressive therapies, with the incidence of HBV reactivation ranging from 40%-60% in those who are positive for Hepatitis B surface antigen (HBsAg). HBV reactivation is preventable with prophylactic antiviral therapy, failing which it can result in delays in cancer treatment, as well as potentially fatal outcomes. Based on recently published data, showing the high risk for HBV reactivation among patients with hematological malignancies receiving B-cell-depleting agents such as RITUXAN® (Rituximab) or ARZERRA® (Ofatumumab), the FDA has urged health care providers to screen all patients for HBV infection, prior to starting therapy with these agents. HBV reactivation has been observed following chemotherapy for solid tumors, but the risk for reactivation in these settings has been unclear with insufficient evidence. The American Society of Clinical Oncology in 2010 rendered a Provisional Clinical Opinion (PCO), suggesting that there was insufficient evidence to determine the net benefits and harms of routine screening for HBV infection, in patients receiving chemotherapy and the recommendation was that screening be considered in those at increased risk for HBV infection or who receive highly immunosuppressive regimens.

This present study was conducted to determine the risk for HBV reactivation with and without antiviral prophylaxis and the benefit of prophylaxis in adults with solid tumors and chronic or resolved HBV infection. This meta-analysis included 26 original reports and the studies were independently reviewed by two investigators for study inclusion. HBV patients included in this study were receiving chemotherapy for any solid tumor with or without concomitant HBV prophylactic therapy. Study patients could receive long-term antiviral treatment or prophylaxis before chemotherapy initiation and the comparison was with those receiving chemotherapy without antiviral prophylaxis. The primary outcome was HBV reactivation as defined by a greater than 10-fold increase in HBV DNA levels from baseline or an absolute increase greater than 105 copies/mL in those with chronic HBV infection or the re-emergence of HBsAg when previously negative, in those with resolved HBV infection. Secondary outcomes included HBV-related hepatitis, interruption or delay in chemotherapy, acute liver failure with coagulopathy and hepatic encephalopathy and death.

It was noted that in patients with chronic HBV infection receiving chemotherapy, the risk for HBV reactivation without antiviral prophylaxis ranged from 4% to 68% (median, 25%). The risk for HBV reactivation, HBV-related hepatitis, and chemotherapy interruption was reduced by more than 80% with antiviral prophylaxis. Interestingly, in patients with resolved HBV infection receiving chemotherapy, there was still a risk of HBV reactivation, with this risk ranging from 0.3% to 9%. The authors in this meta-analysis addressed a very important question and concluded that the risk for HBV reactivation in patients with chronic HBV, on chemotherapy for solid tumors, is similar to the risk with other types of immunosuppressive therapy. Cancer patients should therefore be screened for HBV before chemotherapy is initiated for solid tumors and started on antiviral prophylaxis. Paul S, Saxena A, Terrin N, et al. Hepatitis B Virus Reactivation and Prophylaxis During Solid Tumor Chemotherapy: A Systematic Review and Meta-analysis. Ann Intern Med. 2016; 164:30-40.