FDA expands Xarelto use to DVT, PE

The FDA today voted to expand the approved use of rivaroxaban (Xarelto, Janssen Pharmaceuticals) to include the treatment of deep vein thrombosis or pulmonary embolism.

The drug also now is approved to reduce the risk of recurrence of those two conditions after initial therapy, according to an FDA press release.

“Xarelto is the first oral anti-clotting drug approved to treat and reduce the recurrence of blood clots since the approval of warfarin nearly 60 years ago,” Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said in the release.
The FDA approved the expanded use under its priority review program, which allows for an expedited 6-month review for drugs that offer major advances in treatment or offer a treatment where none exist.
The approval comes after encouraging results from the three EINSTEIN studies, which involved more than 9,000 patients with thromboembolic events.
In July 2011, the FDA approved rivaroxaban to reduce the risk of DVT and PE after knee or hip replacement surgery. In November 2011, the agency approved the drug to reduce stroke risk individuals with non-valvular atrial fibrillation.
thanks HemOnc Today

Olanzapine for Break through nausea and vomiting

Anti-psychotic medication helps control breakthrough CINV

• Thanks HemOnc Today, July 10, 2012

CHICAGO — The anti-psychotic medication olanzapine helps to control breakthrough chemotherapy-induced nausea and vomiting that develops when patients do not respond to conventional prophylactic antiemetic treatments, according to results of a phase 3 trial.

Chemotherapy-induced nausea and vomiting (CINV) affects up to 90% of patients who undergo certain types of chemotherapy, according to background information provided by researchers. About one-third of those patients experience breakthrough CINV.

Olanzapine (Zyprexa, Eli Lily) has been shown to be safe and effective for the prevention of CINV. Researchers hypothesized that olanzapine also may be an effective rescue medication for patients who receive guideline-directed CINV prophylaxis but still experience nausea and vomiting.

Rudolph M. Navari, MD, PhD, clinical director of the Harper Cancer Institute at Indiana University School of Medicine-South Bend, and colleagues conducted a double-blind, randomized controlled trial to compare olanzapine to metoclopramide, which often is prescribed as a treatment for breakthrough CINV despite a lack of research proving its efficacy for that purpose.

Researchers enrolled 205 patients with a median age of 56 years who received guideline-recommended drugs to prevent CINV prior to undergoing their first round of chemotherapy. Eighty of those patients developed breakthrough CINV. Those patients then were randomly assigned to olanzapine 10 mg orally daily for 3 days (n=42) or metoclopramide 10 mg three times a day (n=28) for 3 days. Researchers followed the patients for 72 hours through phone calls from study nurses, and the patients also were asked to keep diaries of their experiences.

Thirty (71%) of the patients assigned to olanzapine experienced no vomiting, compared with 12 (32%) of the patients assigned to metoclopramide, a statistically significant difference. Sixty-seven percent of patients assigned to olanzapine reported experiencing no nausea, compared with 24% of patients assigned to metoclopramide, also a statistically significant difference.

Both treatments were well tolerated, researchers said.

Olanzapine, an FDA-approved treatment for psychosis, causes a variety of side effects when taken daily for 6 months or longer. However, no patients assigned to short-term treatment in this study reported grade-3/grade-4 toxicities, the researchers said.

Because breakthrough CINV typically develops between the second and fourth days after the start of chemotherapy, patients would not have to take olanzapine for longer than 3 days, Navari said in a press release.

“This is the first time that breakthrough CINV has been studied in a systematic way,” Navari said. “This study suggests that olanzapine will be very useful in these patients who feel very sick and sometimes come to the clinic, hospital or emergency room.”

FDA approves enzalutami​de to treat patients with metastatic castration​-resistant prostate cancer who previously received docetaxel

On August 31, 2012, the U. S. Food and Drug Administration approved enzalutamide (XTANDI® Capsules, Medivation, Inc. and Astellas Pharma US, Inc.), for the treatment of patients with metastatic castration-resistant prostate cancer who have previously received docetaxel. 
The approval was based on a single randomized, placebo-controlled, multicenter trial enrolling 1199 patients with metastatic castration-resistant prostate cancer who had received prior docetaxel.  Patients were randomly allocated to receive enzalutamide 160 mg orally once daily (N = 800) or placebo (N = 399).  Study treatment continued until disease progression, initiation of new systemic antineoplastic treatment, unacceptable toxicity, or withdrawal.  Patients were required to continue androgen deprivation therapy and were allowed, but not required, to continue or initiate glucocorticoids during the study period.  Forty-eight percent (48%) of patients on enzalutamide and 46% on placebo received glucocorticoids. 
The primary efficacy endpoint was overall survival (OS).  At the pre-specified interim analysis after 520 events, a statistically significant improvement in OS [HR 0.63 (95% CI: 0.53, 0.75), p < 0.0001, log rank test] was observed.  The median OS was 18.4 and 13.6 months in the enzalutamide and placebo arms, respectively.
The most common (≥5%) grade 1-4 adverse reactions included asthenia or fatigue, back pain, diarrhea, arthralgia, hot flush, peripheral edema, musculoskeletal pain, headache, upper respiratory infection, muscular weakness, dizziness, insomnia, lower respiratory infection, spinal cord compression and cauda equina syndrome, hematuria, paresthesia, anxiety, and hypertension.  Grade 3-4 adverse reactions were reported in 47% of patients treated with enzalutamide and in 53% of those on placebo.
Seizures occurred in 0.9% of patients on enzalutamide.  No patients on the placebo arm experienced seizures.  In the clinical trial, patients experiencing a seizure were permanently discontinued from therapy.  All seizures resolved.  Patients with a history of seizure, taking medications known to decrease the seizure threshold, or with other risk factors for seizures were excluded from the clinical trial.  The safety of enzalutamide in patients with predisposing factors for seizures is unknown. 
The recommended dose and schedule for enzalutamide is 160 mg orally once daily.

New Treatment for Colon Cancer : ziv-aflibercept

On August 3, 2012, the U. S. Food and Drug Administration approved ziv-aflibercept injection (ZALTRAP®, Sanofi U.S., Inc.) for use in combination with 5-fluorouracil, leucovorin, irinotecan (FOLFIRI) for the treatment of patients with metastatic colorectal cancer (mCRC) that is resistant to or has progressed following an oxaliplatin containing regimen.  Ziv-aflibercept (previously known as aflibercept) is a recombinant fusion protein consisting of vascular endothelial growth factor (VEGF)-binding portions from the extracellular domains of human VEGF receptors 1 and 2 that are fused to the Fc portion of the human IgG1 immunoglobulin.  

This approval is based on the results of a randomized, double-blind, placebo-controlled, global, multicenter trial enrolling patients with mCRC that progressed during or within 6 months of receiving oxaliplatin-based combination chemotherapy, with or without prior bevacizumab.

The Phase 3 trial accrued 1226 patients who were randomly allocated (1:1) to receive FOLFIRI (irinotecan 180 mg/m2 IV infusion over 90 minutes, leucovorin 400 mg/m² IV infusion over 2 hours, followed by 5-FU 400 mg/m² IV bolus, followed by 5-FU 2400 mg/m² continuous IV infusion over 46-hours) with either ziv-aflibercept (N=612) or placebo (N=614).  Ziv-aflibercept was administered at a dose of 4 mg/kg IV infusion over 1 hour prior to FOLFIRI.  The treatment cycles on both arms were repeated every 2 weeks.  Patients were treated until disease progression or unacceptable toxicity.  The primary efficacy endpoint was overall survival (OS).  Treatment assignment was stratified by the ECOG performance status and prior exposure to bevacizumab.

Median age of randomized patients was 61 years, 59% were men, and 98% had an ECOG performance status of 0 or 1.  All patients had received prior oxaliplatin treatment.  A statistically significant improvement in OS was observed in patients receiving FOLFIRI plus ziv-aflibercept compared to those receiving FOLFIRI plus placebo [HR 0.82 (95% CI: 0.71, 0.94), p=0.0032, stratified log-rank test].   The median OS was 13.5 and 12.06 months for patients on the ziv-aflibercept and placebo arms, respectively.  Median progression-free survival in the ziv-aflibercept arm was 6.9 compared to 4.7 months in the placebo arm [HR 0.76 (95% CI: 0.66, 0.87), p=0.00007]. 

The most common adverse reactions, (all grades), occurring in greater than or equal to 20%  of patients in the ziv-aflibercept plus FOLFIRI arm (with greater than or equal to 2% difference between arms) were leukopenia, diarrhea, neutropenia, proteinuria, increased AST and ALT, stomatitis, fatigue, thrombocytopenia, hypertension, decreased weight, decreased appetite, epistaxis, abdominal pain, dysphonia, increased serum creatinine, and headache.  The most common grade 3-4 adverse reactions (greater than or equal to 5%) reported at a higher incidence in the ziv-aflibercept plus FOLFIRI arm (greater than or equal to 2% difference between arms) were neutropenia, diarrhea, hypertension, leukopenia, stomatitis, fatigue, proteinuria, and asthenia. 

Severe and sometimes fatal hemorrhages, including gastrointestinal hemorrhages, have been reported in patients receiving ziv-aflibercept.   Grade 3-4 hemorrhagic events occurred in 2.9% of patients receiving FOLFIRI plus ziv-aflibercept compared with 1.7% of those receiving FOLFIRI plus placebo.  In addition to hemorrhage, the ziv-aflibercept label contains a Boxed Warning for the serious adverse reactions gastrointestinal perforation and compromised wound healing. 

Arterial thromboembolic events were observed in 1.7% and 2.6% of patients in the placebo and ziv-aflibercept containing arms, respectively.  Venous thromboembolic events were also observed more frequently with ziv-aflibercept:  9% patients in the ziv-aflibercept-containing arm compared to 7% in the placebo-containing arm.  Fistula formation and reversible posterior leukoencephalopathy syndrome have also been reported in patients who received ziv-aflibercept.

The recommended ziv-aflibercept dose and schedule is 4 mg/kg administered as a 60-minute IV infusion every 2 weeks in combination with the FOLFIRI regimen.

FDA Approves GSK Cancer Drug Votrient For Soft-Tissue Sarcoma

WASHINGTON (Dow Jones)--The Food and Drug Administration on Thursday approved GlaxoSmithKline PLC's (GSK, GSK.LN) cancer drug Votrient for use in patients with soft-tissue sarcoma, making it the first new treatment for the rare type of cancer in decades.

Votrient, a tablet taken orally, is already on the U.S. market to treat advanced kidney cancer. It was approved to treat several subtypes of advanced soft-tissue sarcoma, after prior chemotherapy. The disease starts in muscle or other connective tissues in the body.

The National Cancer Institute estimates there are about 11,000 cases of soft-tissue sarcomas diagnosed in the U.S. each year.

Votrient's approval follows the March recommendation of an agency advisory panel, which voted, 11-2, that the drug's benefits outweighed the risks. Clinical data involving 369 patients showed the drug temporarily slowed tumor growth.

Specifically, the study showed patients being treated with Votrient had a median progression-free survival of 4.6 months compared with 1.6 months on the placebo, or a difference of three months in the time before the cancer starts to worsen.

The FDA noted that Votrient carries the agency's toughest boxed warning, telling patients and health-care professionals about the potential risk of liver damage, which can be fatal. Patients should be monitored for liver function and treatment should be discontinued if liver function declines, the agency said.

The most common side effects seen in Votrient-treated patients were fatigue, diarrhea, nausea, weight loss, high blood pressure, decreased appetite, vomiting, tumor and muscle pain, hair color changes, headache, a distorted sense of taste, shortness of breath, and skin discoloration, the FDA said.

Thanks WSJ

TT

AAP now recommends HPV (Human Papilloma Virus) vaccine for boys and girls

The American Academy of Pediatrics Committee on Infectious Diseases issued an updated policy statement on human papillomavirus vaccination that recommends both boys and girls be immunized.

The policy statement notes vaccination reduces the incidence of sexually transmitted infections and reduces cancer risk.

ancers of the mouth and pharynx, which are increasing in recent years, and of anal and penile cancers.”

There currently is one approved HPV vaccine (HPV4; Gardasil, Merck) for boys and two vaccines — HPV4 and HPV2 (Cervarix, GlaxoSmithKline) — approved for girls.

The committee recommended that:

• Girls aged 11 to 12 years should receive three doses of HPV2 or HPV4 — administered intramuscularly at 0, 1 to 2, and 6 months — even if they already are sexually active.
• Boys aged 11 to 12 years should receive three doses of HPV4 using the same schedule.
• Females aged 13 to 26 years and males aged 13 to 21 years who were not previously immunized or who are missing a vaccination should complete the full series.
• Men aged 22 to 26 years who were not immunized previously or who are missing a vaccination may receive the HPV4 series, but “cost-efficacy models do not justify a stronger recommendation in this age group.”

The policy statement recommended that women who receive the vaccine continue to undergo cervical cancer screening.

About 20 million Americans currently have an HPV infection, and an estimated 7,080 men and 14,720 women develop cancers associated with HPV types 16 and 18 every year, according to the CDC.

An estimated 80% of anal cancers, 65% of vaginal cancers, 50% of vulvar cancers, 35% of penile cancers and nearly all cervical cancers are HPV-related. Roughly 60% of oropharyngeal cancers are associated with HPV.

thanks hemonctoday.com

Tony Talebi, MD

Chemotherapy for Metastatic Colon Cancer

CHEMOTHERAPY FOR UNRESECTABLE COLORECTAL CANCER:

As noted above, surgery is the only way to cure metastatic colorectal cancer. In most cases, surgery is not possible, and chemotherapy is recommended to reduce symptoms and prolong survival. Although chemotherapy provides meaningful improvements in survival, it is not possible to cure metastatic colorectal cancer with chemotherapy alone.

Continuum of care concept — With most types of incurable cancer (other than metastatic colorectal cancer), individual chemotherapy drugs or regimens are given continuously until the cancer stops responding to that drug or regimen, and then an entirely new regimen (termed "second-line therapy") may be tried.

The situation is different with metastatic colorectal cancer because there are many active drugs that can be combined in a number of ways. In addition, treatment-related side effects may be lessened by limiting the number of doses of certain drugs. Thus, instead of giving the first-line regimen until the tumor progresses, treatment is often individualized.

• Specific chemotherapy drugs may be given, stopped, and then restarted at a later time, sometimes in combination with other chemotherapy drugs.
• Periods of aggressive chemotherapy may be interspersed with periods of "maintenance" chemotherapy, allowing the patient to have the greatest possible quality of life while minimizing side effects.

This has been referred to as the "continuum of care" approach to treatment of metastatic colorectal cancer.

Conventional chemotherapy — The conventional chemotherapy drugs used to treat metastatic colorectal cancer include:

• 5-fluorouracil (abbreviated FU), which is usually given into the vein with a second drug called leucovorin, which enhances its activity
• Orally active FU-like drugs, such as capecitabine (Xeloda®)
• Oxaliplatin (Eloxatin®), which is given intravenously
• Irinotecan (Camptosar®), also given intravenously

These drugs work by interfering with the ability of rapidly growing cells (like cancer cells) to divide or reproduce themselves. Because most of an adult's normal cells are not actively growing, they are less affected by chemotherapy, with the exception of bone marrow (where the blood cells are produced), the hair, and the lining of the gastrointestinal tract. Effects of chemotherapy on these and other normal tissues cause side effects during treatment.

Targeted chemotherapy — Three other drugs that are active against metastatic colorectal cancer work by a different mechanism. These are referred to as "targeted chemotherapy agents" since they are antibodies (a type of protein) that work to inhibit a specific protein that is important for the growth and/or survival of colon cancer cells.

Because targeted chemotherapy does not directly interfere with rapidly dividing cells, they do not have the usual side effects of conventional chemotherapy. However, targeted chemotherapy has other unique side effects, which are described in detail below.

Currently available targeted chemotherapy includes:

Bevacizumab (Avastin®) — Bevacizumab binds to a protein called vascular endothelial growth factor (VEGF). VEGF is involved in the development of a blood supply within a growing cancer; this blood supply is essential for the tumor to grow and spread. Bevacizumab enhances the antitumor effect of other chemotherapy drugs. Bevacizumab is not effective when given by itself, but is generally given in combination with other drugs, such as oxaliplatin and irinotecan 

Cetuximab (Erbitux®) — Cetuximab targets a different protein, the epidermal growth factor receptor (EGFR), which is found in about 80 percent of colorectal cancers. Erbitux® is effective even if EGFR is not found in an individual tumor.

Cetuximab does not work for all patients. It depends on whether or not the tumor has a specific abnormality (a mutation in a gene called K-ras).

• If the tumor has a K-ras mutation, cetuximab does not work.
• If the tumor does not have a K-ras mutation, cetuximab does work (ie, it is effective).

Unlike bevacizumab, cetuximab is active when given alone or in combination with other drugs, like irinotecan.

Panitumumab (Vectibix®) — Like cetuximab, panitumumab also targets the EGFR. Like cetuximab, it is effective only for tumors that do not have a specific mutation in the K-ras gene.

Monitoring during treatment — A person's response to chemotherapy is monitored with periodic X-ray studies (such as CT scans) every six to eight weeks during therapy. In addition, blood levels of a tumor marker called carcinoembryonic antigen (CEA) are generally measured every one to three months during therapy. CEA levels are typically high in people with advanced colorectal cancer; persistently rising CEA levels suggest that disease is progressing and a change in therapy is warranted.

However, a rising CEA alone is not sufficient evidence to prompt a change in treatment. Disease progression should be confirmed with radiographic testing (eg, CT scan) or a biopsy before changing treatment.

Thanks uptodate.com

Tony Talebi, MD