SUMMARY: ABRAXANE® (Albumin-bound Paclitaxel or nab-Paclitaxel) is a solvent-free formulation of Paclitaxel with a superior therapeutic index and delivers higher concentrations of the drug’s active ingredient into the tumor cell. This is unlike solvent based taxanes such as TAXOL® (Paclitaxel) and TAXOTERE® (Docetaxel), which have delivery vehicles such as Cremaphor and Polysorbate 80 respectively. By virtue of being solvent free, ABRAXANE® can be administered over a shorter period of time without premedications and is associated with fewer side effects with possibly superior efficacy. In a phase III trial, 1052 treatment naive patients with Stage IIIB/IV Non Small Cell Lung Cancer (NSCLC) were randomly assigned to receive ABRAXANE® 100 mg/m2 weekly and PARAPLATIN® (Carboplatin) at Area Under the Concentration-time curve (AUC) 6, once every 3 weeks (nab-PC) or TAXOL® 200mg/m2 plus PARAPLATIN® AUC 6 once every 3 weeks (sb-PC). Patients were stratified by disease (Stage IIIB vs IV), age (< 70 vs ≥ 70 years), sex (male vs female), histology (squamous vs adenocarcinoma vs others). The primary end point was Overall Response Rate (ORR). Secondary end points included Progression Free Survival (PFS) and Overall Survival (OS). In their original report, the authors concluded that the study met its primary end point and ABRAXANE® combination (nab-PC) significantly improved ORR compared to TAXOL® combination (sb-PC) and was also associated with less neuropathy. In a sub-set analysis of patients 70 years or older (N=156), those in the ABRAXANE® group had a significantly longer median OS compared to the TAXOL® group (19.9 vs 10.4 months, HR=0.58, P=0.009). The PFS in this elderly group trended in favor of ABRAXANE® (8 vs 6.8 months, P=0.13). This survival benefit was not seen in the younger patients. Elderly patients with NSCLC usually tend to have other co-morbidities and treatment can be challenging. With lower incidence of toxicities such as neuropathy, neutropenia and arthralgias, ABRAXANE® combination therapy can be a valuable option for the first line treatment of elderly patients with advanced NSCLC of all histologies. Socinski MA, Langer CJ, Okamoto I, et al. Ann Oncol. 2013;24:314-321
Category: Hem/Onc Updates
Venous Thromboembolism Prophylaxis and Treatment in Patients With Cancer American Society of Clinical Oncology Clinical Practice Guideline Update
SUMMARY: The American Society of Clinical Oncology (ASCO) recently provided recommendations for the prophylaxis and treatment of venous thromboembolism (VTE) in patients with cancer following a systematic review of 42 publications. They are as follows-
VTE prophylaxis in hospitalized patients
Majority of the hospitalized patients with active malignancy should receive VTE prophylaxis in the absence of contraindications. However there are no definitive data for VTE prophylaxis in patients admitted for short chemotherapy infusions, minor procedures or those undergoing stem-cell or bone marrow transplantation.
VTE prophylaxis in ambulatory patients
Routine VTE prophylaxis is not recommended although prophylaxis with low molecular-weight heparin can be considered in select group of outpatients with solid tumors who are receiving chemotherapy, after discussing the risk/benefits of such intervention. Patients with Myeloma receiving THALOMID® (Thalidomide) or REVLIMID® (Lenalidomide) should receive VTE prophylaxis with either aspirin or low molecular-weight heparin.
VTE prophylaxis in patients undergoing surgery
All cancer patients undergoing major surgical procedures should be considered for VTE prophylaxis with heparin unless there is a bleeding risk. This should be commenced preoperatively and can be complemented with mechanical methods to improve efficacy. This should be continued for at least 7-10 days and for up to 4 weeks postoperatively, in those undergoing major abdominal or pelvic surgery with restricted mobility, obesity, history of VTE or additional risk factors. Decision to consider prophylaxis, for patients undergoing low risk surgery, should be made on an individual basis.
Choice of Anticoagulation for cancer patients with VTE
For cancer patients who have a creatinine clearance of more than 30 ml/min and have newly diagnosed VTE , low molecular-weight heparin is preferred over unfractionated heparin for the initial 5 to 10 days. Low molecular-weight heparin, due to its superiority, is preferred over vitamin K antagonists for long term anticoagulation (6 months). Select cancer patients with metastatic disease or those receiving chemotherapy may be considered for anticoagulation with low molecular-weight heparin or vitamin K antagonists beyond the initial 6 months. A vena cava filter is indicated only for patients with contraindications to anticoagulant therapy and may be considered for those who progress despite optimal anticoagulation with low molecular-weight heparin. Patients with CNS malignancies and VTE should be anticoagulated like any other patient with VTE, monitoring closely for bleeding. Incidental VTE’s should be treated like symptomatic VTE. Decision to treat splanchnic or visceral vein thrombi diagnosed incidentally should be considered on an individual basis. The new novel oral anticoagulants are presently not recommended for prophylaxis or treatment of VTE.
Anticoagulation and survival benefit in patients without VTE
Cancer patients without VTE should not receive anticoagulants to improve survival, as there are no data to support this recommendation.
Predicting VTE in cancer patients using Risk Score
The risk score model below for VTE in cancer patients was developed and validated in multiple studies. The risk of VTE can be significantly reduced amongst these high risk patients by thromboprophylaxis
Lyman GH, Khorana AA, Kuderer NM, et al. J Clin Oncol 2013;31:2189-2204
Rituximab Maintenance Therapy Until Progression After Rituximab and Chemotherapy Induction in Patients With Follicular Lymphoma
SUMMARY: In this intriguing analysis, the authors reported the outcomes, when patients with low grade Follicular Lymphoma received maintenance RITUXAN® (Rituximab) beyond 2 years. The randomized, PRIMA (Primary Rituximab and Maintenance) study established that 2 years of RITUXAN® maintenance therapy after a RITUXAN® plus chemotherapy regimen, as first-line treatment for follicular lymphoma, significantly improves Progression Free Survival (PFS). The decision to give 2 years of maintenance RITUXAN® in the PRIMA study was arbitrary. It is estimated however that over 30% of the patients receiving 2 yrs of maintenance RITUXAN®, relapse at 3 years and beyond. The authors in this single institution study analyzed clinical data on 25 consecutive, unselected, treatment naïve patients with biopsy-proven diagnosis of Follicular Lymphoma. All these patients had a high tumor burden, with at least one indication for initiation of systemic therapy, which included B symptoms, cytopenia(s), bulky disease, disease progression, or impending organ damage. These patients achieved a Partial Response (PR) or a Complete Response (CR), after systemic induction treatment and subsequently received Maintenance RITUXAN® indefinitely or until disease progression. The median follow up was 5 years. The PFS in this group was 100% and 5 year overall survival was 82%. Forty five percent (45%) of the patients who achieved PR improved to CR on Maintenance RITUXAN® treatment. This benefit was accomplished with minimal toxicity with no additional complications related to hypogammaglobinemia. The authors concluded that Maintenance RITUXAN® beyond the arbitrary 2 years, is safe and may result in prolonged PFS in responding patients following chemoimmunotherapy. This provocative data begs the question whether maintenance RITUXAN® should be continued until disease progression rather than stopping at the 2 year arbitrary time frame. Yared J, Kimball A, Baer MR, et al. Clinical Lymphoma Myeloma and Leukemia 2013;13:253-257
ICON7 Final overall survival results in the GCIG phase III randomized trial of bevacizumab in women with newly diagnosed ovarian cancer
SUMMARY: ICON7 is a randomized phase III trial in which the safety and efficacy of combining AVASTIN® (Bevacizumab) with standard chemotherapy was evaluated in patients with Newly Diagnosed Ovarian Cancer. One thousand five hundred and twenty eight (n=1528) patients with high-risk (grade 3 or clear cell histology) stage I-IIa or stage IIb-IV epithelial ovarian, primary peritoneal or fallopian tube cancer, were randomized to receive either 6 cycles of combination chemotherapy with PARAPLATIN® (Carboplatin) AUC of 5 or 6 and TAXOL® (Paclitaxel) 175mg/m2 given every 3 weeks or the same chemotherapy regimen given concurrently with AVASTIN® (Bevacizumab) 7.5mg/kg, every 3 weeks for 5 or 6 cycles followed maintenance AVASTIN® for 12 additional cycles or until disease progression, whichever was the earlier. The median age was 57 years. Approximately 33% of the patients randomized were considered poor prognosis group, at high risk for progression. At the first interim analysis, the addition of AVASTIN® to standard chemotherapy, followed by maintenance AVASTIN® demonstrated improved Progression Free Survival (PFS) compared to standard chemotherapy alone (19 vs17.3 months, P=0.0041). In the planned Final analysis, at a median follow up of 49 months, the PFS superiority in the AVASTIN® group was maintained, similar to the first analysis but there was no improvement in the median Overall Survival (OS) between the two treatment groups. However, in the predefined high-risk, poor prognostic subgroup of patients, AVASTIN® improved OS by 4.8 months, without any major adverse events. The authors concluded that the addition of AVASTIN® to standard chemotherapy can translate into clinically meaningful survival benefit, for patients with high risk disease. Oza AM, Perren TJ, Swart AM, et al. European Cancer Congress. Abstract 6. Presented on September 29, 2013.
Bevacizumab plus capecitabine versus capecitabine alone in elderly patients with previously untreated metastatic colorectal cancer (AVEX) an open-label, randomised phase 3 trial
SUMMARY: The authors in this randomized phase III trial specifically enrolled chemo naïve patients, 70 years of age or older, with metastatic ColoRectal Cancer (CRC) because, this sub group of patients are often excluded or under- represented in clinical trials. Two hundred and eighty (N=280) chemo naïve patients with metastatic CRC, deemed not to be candidates for more aggressive regimens such as ELOXATIN® (Oxaliplatin) or CAMPTOSAR® (Irinotecan) based chemotherapy regimens, were randomly assigned in a 1:1 ratio to receive either AVASTIN® (Bevacizumab) plus XELODA® (Capecitabine) (n=140) or XELODA® alone (n=140). Treatment consisted of XELODA® 1000 mg/m2 orally twice a day on days 1—14 alone or with AVASTIN® 7•5 mg/kg, given intravenously on day 1. Treatment was given every 3 weeks until disease progression or until unacceptable toxicities were noted. The median age was 76 years and patients were stratified by performance status. The median number of cycles for AVASTIN® plus XELODA® was 9 and for XELODA® alone was 6 cycles. The primary endpoint was Progression Free Survival (PFS). The PFS was significantly longer with the combination of AVASTIN® and XELODA® versus XELODA® alone (9•1 months vs 5•1 months; Hazard Ratio= 0•53; P<0•0001). The combination treatment in general was well tolerated but with a slightly higher incidence of hand-foot syndrome and hemorrhage compared to single agent XELODA®. Overall Survival (OS) was not significantly different between the treatment groups as this study was not powered to detect OS differences. The authors concluded that, in this study, which only enrolled elderly patients with metastatic CRC, unsuitable for aggressive therapy, a combination of AVASTIN® and XELODA® is a reasonable option with proven benefit. Cunningham D, Lang I, Marcuello E, et al. Lancet Oncol 2013;14:1077-1085
Crizotinib versus Chemotherapy in Advanced ALK-Positive Lung Cancer
SUMMARY: EML4-ALK (Echinoderm Microtubule associated protein Like 4) – ALK (Anaplastic Lymphoma Kinase) is an aberrant fusion-type oncoprotein and is a tyrosine kinase. This oncoprotein/tyrosine kinase is found in 2-7% of all Non Small Cell Lung Cancers (NSCLC) and is generated due to an inversion in the short arm of chromosome 2. This oncoprotein is more prevalent in patients with adenocarcinoma, who have little or no exposure to tobacco. Tyrosine kinases normally play an important role in cellular proliferation and differentiation. However with point mutations, translocation/rearrangement and amplification of the respective genes, the associated tyrosine kinases can potentially cause malignancy. Such is the case with mutations or translocations of the Anaplastic Lymphoma Kinase gene (ALK). Crizotinib (XALKORI®) is a small molecule Tyrosine Kinase Inhibitor that targets ALK, MET and ROS1 tyrosine kinases. In this open label phase III trial, 347 patients with locally advanced or metastatic ALK-positive lung cancer who had received one prior platinum based regimen, were randomly assigned to receive XALKORI® 250 mg PO twice daily (N=173) or intravenous chemotherapy with either Pemetrexed (ALIMTA®) 500 mg/m2 or Docetaxel (TAXOTERE®) 75 mg/m2, every 3 weeks (N=174). The primary endpoint was Progression Free Survival (PFS) and secondary endpoints included Overall Survival (OS), Response Rate (RR) and safety. The median PFS was 7.7 months in the XALKORI® group as compared to 3 months in the chemotherapy group (HR=0.49; P<0.001). The Response Rates for XALKORI® and chemotherapy were 65% and 20% respectively (P<0.001). At the time of interim analysis, there was no significant difference in the OS between the XALKORI® and chemotherapy groups. The authors pointed out that this lack of OS benefit was due to the high cross over rate to the XALKORI® group from the chemotherapy group. Patients in the XALKORI® group had better quality of life, greater reduction in lung cancer symptoms and were on the study treatment longer, than with chemotherapy. The authors concluded that XALKORI® improves PFS, Response Rates as well as Quality Of Life in patients with previously treated, ALK positive advanced Non Small Cell Lung Cancer. This is remarkable, considering that the response rates in this patient population treated with second line chemotherapy is around 10-15%. As we move forward, it is very likely that tailored therapy based on molecular genotyping will become standard practice. Shaw AT, Kim D, Nakagawa K, et al. N Engl J Med 2013; 368:2385-2394
GAZYVA® plus LEUKERAN® – A new option for elderly patients with CLL
Obinutuzumab or GAZYVA® (GA101) is glycoengineered, fully humanized, third generation, type II anti-CD20 antibody (IgG1 monoclonal antibody) that selectivity binds to the extracellular domain of the CD20 antigen on malignant human B cells. It has enhanced antibody-dependent cellular cytotoxicity (ADCC) and strong apoptosis-inducing activity. In contrast, RITUXAN® (Rituximab) is a first generation chimeric anti-CD20 targeted monoclonal antibody. In a phase III trial, a combination of GAZYVA® plus LEUKERAN® (Chlorambucil), significantly improved Progression Free Survival in elderly patients with CLL compared to RITUXAN® plus LEUKERAN®. This study gives new life to LEUKERAN® when given in combination with CD20 targeted monoclonal antibodies and may be of value when treating elderly patients with comorbid conditions. This data was presented at the 2013 ASCO meeting.
Sorafenib in locally advanced or metastatic patients with radioactive iodine-refractory differentiated thyroid cancer The phase III DECISION trial
SUMMARY: The FDA approved Sorafenib (NEXAVAR®) for the treatment of patients with locally recurrent or metastatic, progressive, Differentiated Thyroid Carcinoma (DTC), refractory to RadioActive Iodine (RAI) treatment. Over 90% of all thyroid cancers are classified as Differentiated Thyroid Cancers with Papillary, Follicular and Hürthle cell histologies. NEXAVAR® inhibits multiple kinases that are involved in cell proliferation and angiogenesis thereby preventing cancer growth. These kinases include Raf, VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-B, KIT, FLT-3 and RET. The DECISION trial is a randomized, double-blind, multicenter phase III study in which the efficacy and safety of NEXAVAR® was compared with placebo, in patients with progressive RAI-refractory DTC. Four hundred and seventeen patients (417) were randomized to receive either NEXAVAR® 400 mg po BID (n=207) or placebo (n=210). The median age was 63 yrs and only patients who had no prior chemotherapy or targeted therapy and with disease progression within the preceding 14 months, were included. Over 95% of the patients had metastatic disease and the most common sites of spread were lungs and lymph nodes. Treatment was continued until disease progression or until unacceptable toxicity was noted. Upon progression, patients in the placebo group were allowed to crossover and receive open-label NEXAVAR®. The primary endpoint was Progression Free Survival (PFS). Secondary endpoints included Overall Survival (OS), Response Rate (RR=Complete + Partial Response [PR]), and safety. Approximately 70% of patients in the placebo arm were allowed to crossover to receive open-label NEXAVAR®. The median PFS was 10.8 months with NEXAVAR® compared to 5.8 months with placebo (hazard ratio [HR] = 0.58; P <0.0001). Partial responses were observed in 12.2% of patients receiving NEXAVAR® compared with 0.5% in the placebo arm (P < 0.0001). Further, 42% of patients in the NEXAVAR® group had stable disease for 6 months or more compared to 33% in the placebo group. Median OS has not been reached. The most common adverse events in the NEXAVAR® group included hand–foot skin reaction, diarrhea, rash/desquamation, fatigue and hypertension. The authors concluded that NEXAVAR® extends PFS in a select group of patients with advanced DTC and is the first and only FDA approved therapy for DTC. Brose MS, Nutting C, Jarzab B, et al. J Clin Oncol 31, 2013 (suppl; abstr 4)
Sorafenib in locally advanced or metastatic patients with radioactive iodine-refractory differentiated thyroid cancer The phase III DECISION trial
SUMMARY: The FDA approved Sorafenib (NEXAVAR®) for the treatment of patients with locally recurrent or metastatic, progressive, Differentiated Thyroid Carcinoma (DTC), refractory to RadioActive Iodine (RAI) treatment. Over 90% of all thyroid cancers are classified as Differentiated Thyroid Cancers with Papillary, Follicular and Hürthle cell histologies. NEXAVAR® inhibits multiple kinases that are involved in cell proliferation and angiogenesis thereby preventing cancer growth. These kinases include Raf, VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-B, KIT, FLT-3 and RET. The DECISION trial is a randomized, double-blind, multicenter phase III study in which the efficacy and safety of NEXAVAR® was compared with placebo, in patients with progressive RAI-refractory DTC. Four hundred and seventeen patients (417) were randomized to receive either NEXAVAR® 400 mg po BID (n=207) or placebo (n=210). The median age was 63 yrs and only patients who had no prior chemotherapy or targeted therapy and with disease progression within the preceding 14 months, were included. Over 95% of the patients had metastatic disease and the most common sites of spread were lungs and lymph nodes. Treatment was continued until disease progression or until unacceptable toxicity was noted. Upon progression, patients in the placebo group were allowed to crossover and receive open-label NEXAVAR®. The primary endpoint was Progression Free Survival (PFS). Secondary endpoints included Overall Survival (OS), Response Rate (RR=Complete + Partial Response [PR]), and safety. Approximately 70% of patients in the placebo arm were allowed to crossover to receive open-label NEXAVAR®. The median PFS was 10.8 months with NEXAVAR® compared to 5.8 months with placebo (hazard ratio [HR] = 0.58; P <0.0001). Partial responses were observed in 12.2% of patients receiving NEXAVAR® compared with 0.5% in the placebo arm (P < 0.0001). Further, 42% of patients in the NEXAVAR® group had stable disease for 6 months or more compared to 33% in the placebo group. Median OS has not been reached. The most common adverse events in the NEXAVAR® group included hand–foot skin reaction, diarrhea, rash/desquamation, fatigue and hypertension. The authors concluded that NEXAVAR® extends PFS in a select group of patients with advanced DTC and is the first and only FDA approved therapy for DTC. Brose MS, Nutting C, Jarzab B, et al. J Clin Oncol 31, 2013 (suppl; abstr 4)
Hereditary Hemochromatosis Missed Diagnosis or Misdiagnosis?
SUMMARY: The authors in this provocative study reviewed the electronic medical records of patients seen at a tertiary referral center, to evaluate the accuracy of diagnosis of Hereditary Hemochromatosis (HH), an Autosomal Recessive disorder. The HFE gene is located on the short arm of chromosome 6 and modulates iron uptake. HFE genotyping helps differentiate HH from secondary causes of Iron overload syndromes. This differentiation is relevant because of the lack of established guidelines with regards to management of individuals with abnormal iron studies, secondary to liver disease. It is however well known that HH and iron overload related to transfusions, can cause organ damage and this could be prevented by removing the excess iron. In this study, the authors investigated the diagnostic approach, when elevated iron studies were noted, interpretation of HFE genotyping results by physicians in order to accurately diagnose HH and factors contributing to misdiagnosis. This chart review conducted between January 2002 and May 2012 demonstrated that of the 601 patients with disorders of iron metabolism, only 62% were genotyped for mutations in the HFE gene. Of those genotyped, 54% had genotypes consistent with HH (Homozygotes – C282Y/C282Y or Compound Heterozygotes – C282Y/H63D) and the rest of the 46% had non hereditary hemochromatosis genotypes (C282Y heterozygotes, H63D homozygotes and heterozygotes, etc). One half of these non hereditary hemochromatosis genotype patients were misdiagnosed with HH and a third of these patients underwent phlebotomy. Of those who were not genotyped for mutations in the HFE gene, a third of these patients were diagnosed to have HH and majority of these patients underwent phlebotomy. More than 2/3rd of the patients misdiagnosed to have HH in fact had liver disease and 5% had other hematological conditions. The authors concluded that C282Y heterozygotes as well as H63D homozygotes and heterozygotes do not have HH and a majority of patients with iron overload are misdiagnosed to have HH. Aggressive phlebotomy in the absence of an appropriate Hereditary Hemochromatosis genotype, is not indicated and can be potentially harmful, delaying more appropriate therapy. Cherfane CE, Hollenbeck RD, Go J, et al. The American Journal of Medicine 2013;126:1010-1015.